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12 December 2012
EMA/119871/2012
Guideline on good pharmacovigilance practices (GVP)
Module III – Pharmacovigilance inspections
Draft finalised by the Agency in collaboration with Member States and
submitted to ERMS FG
25 May 2012
Draft agreed by ERMS FG 30 May 2012
Draft adopted by Executive Director 22 June 2012
Start of public consultation 27 June 2012
End of consultation (deadline for comments) 24 August 2012
Revised draft in collaboration with Member States 23 November 2012
Revised draft agreed by ERMS FG 6 December 2012
Revised draft adopted by Executive Director as final 12 December 2012
Date for coming into effect 13 December 2012
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TABLE OF CONTENTS
III.A. Introduction ...................................................................................... 3
III.B. Structures and processes ................................................................... 4
III.B.1. Inspection types .............................................................................................. 4
III.B.1.1. System and product-related inspections........................................................... 4
III.B.1.2. Routine and “for cause” pharmacovigilance inspections ...................................... 5
III.B.1.3. Pre-authorisation inspections .......................................................................... 6
III.B.1.4. Post-authorisation inspections ........................................................................ 7
III.B.1.5. Announced and unannounced inspections ........................................................ 7
III.B.1.6. Re-inspections .............................................................................................. 7
III.B.1.7. Remote inspections ....................................................................................... 7
III.B.2. Inspection planning .......................................................................................... 8
III.B.3. Sites to be inspected ........................................................................................ 9
III.B.4. Inspection scope .............................................................................................. 9
III.B.4.1. Routine pharmacovigilance inspections .......................................................... 10
III.B.4.2. For cause inspections .................................................................................. 11
III.B.4.3. Re-inspections ............................................................................................ 11
III.B.5. Inspection process ......................................................................................... 12
III.B.6. Inspection follow-up ....................................................................................... 12
III.B.7. Regulatory actions and sanctions ..................................................................... 13
III.B.8. Record management and archiving .................................................................. 14
III.B.9. Qualification and training of inspectors ............................................................. 14
III.B.10. Quality management of pharmacovigilance inspection process ........................... 15
III.C. Operation of the EU network ............................................................ 15
III.C.1. Sharing of information .................................................................................... 15
III.C.2. Role of the European Medicines Agency ............................................................ 15
III.C.2.1. General Role of the Agency .......................................................................... 15
III.C.2.2. Role of the PRAC ......................................................................................... 16
III.C.2.3. Role of the CHMP ........................................................................................ 16
III.C.3. Role of the Commission .................................................................................. 16
III.C.4. Role of the Member States .............................................................................. 17
III.C.5. Role of the Marketing Authorisation Holders and Applicants ................................ 18
III.C.6. Inspection Fees ............................................................................................. 19
III.C.7. Transparency ................................................................................................ 19
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III.A. Introduction
This Module contains guidance on the planning, conduct, reporting and follow-up of pharmacovigilance
inspections in the EU and outlines the role of the different parties involved. General guidance is
provided under III.B., while III.C. covers the overall operation of pharmacovigilance inspections in the
EU.
In order to determine that marketing authorisation holders comply with pharmacovigilance obligations
established within the EU, and to facilitate compliance, competent authorities of the Member States
concerned shall conduct, in cooperation with the Agency, pharmacovigilance inspections of marketing
authorisation holders or any firms employed to fulfil marketing authorisation holder’s
pharmacovigilance obligations. Such inspections shall be carried out by inspectors appointed by the
national competent authorities and empowered to inspect the premises, records, documents and
pharmacovigilance system master file (PSMF) of the marketing authorisation holder or any firms
employed by the marketing authorisation holder to perform the activities described in Title IX of
Directive 2001/83/EC in accordance with articles 111(1) and 111(1)(d) (Directive is referenced as
DIR). In particular, marketing authorisation holders are required to provide, on request, the
pharmacovigilance system master file, which will be used to inform inspection conduct [DIR Art 23(4)
and Regulation (EC) No 726/2004 article 16(4) (Regulation is referenced as REG) (see Module II).
The objectives of pharmacovigilance inspections are:
to determine that the marketing authorisation holder has personnel, systems and facilities in place
to meet their pharmacovigilance obligations;
to identify, record and address non-compliance which may pose a risk to public health;
to use the inspection results as a basis for enforcement action, where considered necessary.
For marketing authorisation holders of centrally authorised products, it is the responsibility of the
supervisory authority for pharmacovigilance to verify, on behalf of the EU, that the marketing
authorisation holder for the medicinal product satisfies the pharmacovigilance requirements laid down
in Directive 2001/83/EC [REG Art 19]. The supervisory authority for pharmacovigilance shall be the
competent authority of the Member State in which the pharmacovigilance system master file is located
[REG Art 18(3)]. According to article 7(1) of the Commission Implementation Regulation (EU) No
520/2012 (Implementing Regulation is referenced as IR) the pharmacovigilance system master file
shall be located either at the site in the Union where the main pharmacovigilance activities of the
marketing authorisation holder are performed or at the site in the Union where the qualified person
responsible for pharmacovigilance operates. The supervisory authority may conduct pre-authorisation
inspections to verify the accuracy and successful implementation of the existing or proposed
pharmacovigilance system [REG Art 18(3)].
For marketing authorisation holders of non-centrally authorised products (i.e. nationally authorised
products, including those authorised through the mutual recognition or the decentralised procedure), it
is the responsibility of the competent authority of the Member State concerned, in cooperation with the
Agency, to ensure by means of inspection that the legal requirements governing medicinal products
are complied with. This cooperation shall consist of the sharing of information between national
competent authorities and the Agency concerning inspections that are planned and those that have
been conducted [DIR Art 111(1)].
Pharmacovigilance inspection programmes will be implemented, which will include routine inspections
scheduled according to a risk-based approach and will also incorporate “for cause” inspections, which
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have been triggered to examine suspected non-compliance or potential risks, usually with impact on a
specific product(s).
There shall be cooperation between national competent authorities and the Agency to minimise
duplication and maximise the use of available resources. National competent authorities and the
Agency will make use of the shared information on planned and conducted inspections to facilitate this
and to adapt the scope and/or timing of their inspections.
The results of an inspection will be provided to the inspected entity [DIR Art 111(3) and 111(8)], who
will be given the opportunity to comment on any non-compliance identified [DIR Art 111(8)]. Any non-
compliance should also be rectified by the marketing authorisation holder in a timely manner through
the implementation of a corrective and preventive action plan.
If the outcome of the inspection is that the marketing authorisation holder does not comply with the
pharmacovigilance obligations, the Member State concerned shall inform the other Member States, the
Agency and the Commission in accordance with section III.C.1 [DIR Art 111(8)].
Sharing of information and communication between inspectors and assessors from the
Pharmacovigilance Risk Assessment Committee (PRAC) and from the Committee for Medicinal Products
for Human Use (CHMP), is very important in relation to issues of Union interest and, where considered
appropriate, for the proper follow-up of inspections and the provision of recommendations on actions
to be taken.
Where appropriate, the Member State concerned shall take the necessary measures to ensure that a
marketing authorisation holder is subject to effective, proportionate and dissuasive penalties [DIR Art
111(8)]. Regulation (EC) No 658/2007 also empowers the Commission to impose financial penalties on
marketing authorisations holders to ensure the enforcement of certain obligations connected with
marketing authorisations for medicinal products granted in accordance with Regulation (EC) No
726/2004.
Information on the conduct and outcome of pharmacovigilance inspections and the follow-up and
evaluation of the consequences may be made publicly available as part of the overall transparency of
pharmacovigilance activities.
III.B. Structures and processes
III.B.1. Inspection types
III.B.1.1. System and product-related inspections
Pharmacovigilance system inspections are designed to review the procedures, systems, personnel, and
facilities in place and determine their compliance with regulatory pharmacovigilance obligations. As
part of this review, product specific examples may be used to demonstrate the operation of the
pharmacovigilance system.
Product-related pharmacovigilance inspections are primarily focused on product-related
pharmacovigilance issues, including product-specific activities and documentation, rather than a
general system review. Some aspects of the general system may still be examined as part of a
product-related inspection (e.g. the system used for that product).
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III.B.1.2. Routine and “for cause” pharmacovigilance inspections
Routine pharmacovigilance inspections are inspections scheduled in advance as part of inspection
programmes. There is no specific trigger to initiate these inspections, although a risk-based approach
to optimize supervisory activities should be implemented. These inspections are usually system
inspections but one or more specific products may be selected as examples to verify the
implementation of the system and to provide practical evidence of its functioning and compliance.
Particular concerns, e.g. raised by assessors, may also be included in the scope of a routine inspection,
in order to investigate the specific issues.
For cause pharmacovigilance inspections are undertaken when a trigger is recognised, and an
inspection is considered an appropriate way to examine the issues. For cause inspections are more
likely to focus on specific pharmacovigilance processes or to include an examination of identified
compliance issues and their impact for a specific product. However, full system inspections may also be
performed resulting from a trigger. For cause inspections may arise when, for example, one or more of
the triggers listed below are identified:
risk-benefit balance of the product:
change in the risk-benefit balance where further examination through an inspection is
considered appropriate;
delays or failure to identify or communicate a risk or a change in the risk-benefit balance;
communication of information on pharmacovigilance concerns to the general public without
giving prior or simultaneous notification to the national competent authorities or Agency, as
applicable;
non-compliance or product safety issues identified during the monitoring of pharmacovigilance
activities by the national competent authorities and/or the Agency;
suspension or product withdrawal with no advance notice to the competent authorities;
reporting obligations (expedited and periodic):
delays or omissions in reporting;
poor quality or incomplete reports;
inconsistencies between reports and other information sources;
requests from competent authorities:
failure to provide the requested information or data within the deadline specified by the
competent authorities;
poor quality or inadequate provision of data to fulfil requests for information from the
competent authorities;
fulfilment of commitments:
concerns about the status or fulfilment of risk management plan (RMP) commitments;
delays or failure to carry out specific obligations relating to the monitoring of product safety,
identified at the time of the marketing authorisation;
poor quality of reports requested as specific obligations;
inspections:
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delays in the implementation or inappropriate implementation of corrective and preventive
actions;
information such as non-compliance or product safety issues from other types of inspections
(GCP, GMP, GLP and GDP) ;
inspection information received from other authorities (EU or non-EU), which may highlight
issues of non-compliance;
others:
concerns following review of the pharmacovigilance system master file;
non-inspection related information received from other authorities, which may highlight issues
of non-compliance;
other sources of information or complaints.
III.B.1.3. Pre-authorisation inspections
Pre-authorisation pharmacovigilance inspections are inspections performed before a marketing
authorisation is granted. These inspections are conducted with the intent of examining the existing or
proposed pharmacovigilance system as it has been described by the applicant in support of the
marketing authorisation application [REG Art 19]. Pre-authorisation inspections are not mandatory, but
may be requested in specific circumstances. Principles and procedures for requesting pre-authorisation
inspections should be developed to avoid performing unnecessary inspections which may delay the
granting of a marketing authorisation. The following aspects shall be considered during the validation
phase and/or early during the assessment phase:
the applicant has not previously operated a pharmacovigilance system within the EU or is in the
process of establishing a new pharmacovigilance system;
previous information (e.g. inspection history and non-compliance notifications or information from
other authorities) indicates that the applicant has a poor history or culture of compliance. If the
marketing authorisation holder has a history of serious and/or persistent pharmacovigilance non-
compliance, a pre-authorisation pharmacovigilance inspection may be one mechanism to confirm
that improvements have been made to the system before a new authorisation is granted;
due to product-specific safety concerns, it may be considered appropriate to examine the
applicant’s ability:
to implement product specific risk-minimisation activities; or
to meet specific safety conditions which may be imposed; or
to manage routine pharmacovigilance for the product of concern (e.g. anticipated significant
increase in adverse reaction reports when compared to previous products).
In most cases, a risk assessment based on a combination of product-specific and system-related issues
should be performed before a pre-authorisation pharmacovigilance inspection is requested.
If the outcome of the pre-authorisation inspection raises concerns about the applicant’s ability to
comply with the requirements laid down in the Regulation and the Directive, the following
recommendations may be considered:
non approval of the marketing authorisation;
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a re-inspection prior to approval of the marketing authorisation to confirm that critical findings and
recommendations have been addressed;
granting of the marketing authorisation with the recommendation to perform an early post-
authorisation pharmacovigilance inspection. In this case, the findings would influence the timing of
an inspection conducted as part of the EU routine programme of pharmacovigilance inspections
(see III.B.2.);
imposition of safety conditions to the marketing authorisation based on DIR Art 21a and REG Art
14.8.
III.B.1.4. Post-authorisation inspections
Post-authorisation pharmacovigilance inspections are inspections performed after a marketing
authorisation is granted and are intended to examine whether the marketing authorisation holder
complies with its pharmacovigilance obligations. They can be any of the types mentioned under
III.B.1.1 and IIIB.1.2.
III.B.1.5. Announced and unannounced inspections
It is anticipated that the majority of inspections will be announced i.e. notified in advance to the
inspected party, to ensure the availability of relevant individuals for the inspection. However, on
occasion, it may be appropriate to conduct unannounced inspections or to announce an inspection at
short notice (e.g. when the announcement could compromise the objectives of the inspection or when
the inspection is conducted in a short timeframe due to urgent safety reasons).
III.B.1.6. Re-inspections
A re-inspection may be conducted on a routine basis as part of a routine inspection programme. Risk
factors will be assessed in order to prioritise re-inspections. Early re-inspection may take place where
significant non-compliance has been identified and where it is necessary to verify actions taken to
address findings and to evaluate ongoing compliance with the obligations, including evaluation of
changes in the pharmacovigilance system. Early re-inspection may also be appropriate when it is
known from a previous inspection that the inspected party had failed to implement appropriately
corrective and preventive actions in response to an earlier inspection.
III.B.1.7. Remote inspections
These are pharmacovigilance inspections performed by inspectors remote from the premises of the
marketing authorisation holder or firms employed by the marketing authorisation holder.
Communication mechanisms such as the internet or telephone may be used in the conduct of the
inspection. For example, in cases where key sites for pharmacovigilance activities are located outside
the EU or a third party service provider is not available at the actual inspection site, but it is feasible to
arrange interviews of relevant staff and review of documentation, including the safety database, source
documents and pharmacovigilance system master file, via remote access. This approach may also be
taken where there are logistical challenges to an on-site inspection during exceptional circumstances
(e.g. a pandemic outbreak or travel restrictions). Such approaches are taken at the discretion of the
inspectors and in agreement with the body commissioning the inspection. The logistical aspects of the
remote inspection should be considered following liaison with the marketing authorisation holder.
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Where feasible, a remote inspection may lead to a visit to the inspection site if it is considered that the
remote inspection has revealed issues which require on-site inspection or if the objectives of the
inspection could not be met by remote inspection.
III.B.2. Inspection planning
Pharmacovigilance inspection planning should be based on a systematic and risk-based approach to
make the best use of surveillance and enforcement resources whilst maintaining a high level of public
health protection. A risk-based approach to inspection planning will enable the frequency, scope and
breadth of inspections to be determined accordingly.
In order to ensure that inspection resources are used in an efficient way, the scheduling and conduct of
inspections will be driven by the preparation of inspection programmes. Sharing of information and
communication between inspectors and assessors is important to ensure successful prioritisation and
targeting of these inspections.
Factors which may be taken into consideration, as appropriate, by the competent authorities when
establishing pharmacovigilance inspection programmes include, but are not limited to:
inspection related:
compliance history identified during previous pharmacovigilance inspections or other types of
inspections (GCP, GMP, GLP and GDP);
re-inspection date recommended by the inspectors or assessors as a result of a previous
inspection;
product related:
product with additional pharmacovigilance activities or risk-minimisation activities;
authorisation with conditions associated with safety, e.g. requirement for post-authorisation
safety studies (PASS) or designation for additional monitoring;
product(s) with large sales volume, i.e. products associated with large patient exposure in the
EU;
product(s) with limited alternative in the market place;
Marketing authorisation holder related:
marketing authorisation holder that has never been subject to a pharmacovigilance inspection;
marketing authorisation holder with many products on the market in the EU;
resources available to the marketing authorisation holder for the pharmacovigilance activities
they undertake;
marketing authorisation holder with no previous marketing authorisations in the EU;
negative information and/or safety concerns raised by competent authorities, other bodies
outside the EU or other areas (i.e. GCP, GMP, GLP and GDP);
changes in the marketing authorisation holder organisation, such as mergers and acquisitions;
pharmacovigilance system related:
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marketing authorisation holder with sub-contracted pharmacovigilance activities (function of
the qualified person responsible for pharmacovigilance in the EU (QPPV), reporting of safety
data etc.) and/or multiple firms employed to perform pharmacovigilance activities;
change of QPPV since the last inspection;
changes to the pharmacovigilance safety database(s), which could include a change in the
database itself or associated databases, the validation status of the database as well as
information about transferred or migrated data;
changes in contractual arrangements with pharmacovigilance service providers or the sites at
which pharmacovigilance is conducted;
delegation or transfer of pharmacovigilance system master file management.
National competent authorities and the Agency may solicit information from marketing authorisation
holders for risk-based inspection planning purposes if it is not readily available elsewhere.
III.B.3. Sites to be inspected
Any party carrying out pharmacovigilance activities in whole or in part, on behalf of, or in conjunction
with the marketing authorisation holder may be inspected, in order to confirm their capability to
support the marketing authorisation holder’s compliance with pharmacovigilance obligations.
The sites to be inspected may be located in the EU (e.g. EU QPPV site) or outside the EU. Inspections
of sites outside the EU might be appropriate where the main pharmacovigilance centre, databases
and/or activities are located outside the EU and it would be otherwise inefficient or impossible to
confirm compliance from a site within the EU. Member States and the Agency shall cooperate in the
coordination of inspections in third countries [DIR Art 111(1)].
The type and number of sites to be inspected should be selected appropriately to ensure that the key
objectives within the scope of the inspection are met.
III.B.4. Inspection scope
The inspection scope will depend on the objectives of the inspection as well as the coverage of any
previous inspections by competent authorities of Member States and whether it is a system or product-
related inspection (a description of the types of inspection, inspection triggers and points to consider
for the different types of inspection is provided in III.B.1.).
The following elements should be considered when preparing the scope of the inspection, as
applicable:
information supplied in the pharmacovigilance system master file;
information concerning the functioning of the pharmacovigilance system, e.g. compliance data
available from the Agency such as EudraVigilance reporting and data quality audits;
specific triggers (see III.B.1.2. for examples of triggers);
It may be appropriate for additional data to be requested in advance of an inspection in order to select
appropriate sites or clarify aspects of the pharmacovigilance system.
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III.B.4.1. Routine pharmacovigilance inspections
Routine pharmacovigilance inspections conducted on behalf of the EU should examine compliance with
EU legislation and guidance, and the scope of such inspections should include the following elements,
as appropriate:
individual case safety reports (ICSRs):
collecting, receiving and exchanging reports - from all types of sources, sites and departments
within the pharmacovigilance system, including from those firms employed to fulfil marketing
authorisation holder’s pharmacovigilance obligations and departments other than drug safety;
assessment, including mechanisms for obtaining and recording reporter assessments, company
application of event terms, seriousness, expectedness and causality. In addition to examples of
ICSRs from within the EU, examples of ICSRs reported from outside the EU should be
examined as part of this review (if applicable);
follow-up and outcome recording, for example final outcome of cases of exposure in pregnancy
and medical confirmation of consumer reported events;
reporting according to the requirements for various types of reported ICSRs, including onward
reporting to the relevant bodies and timeliness of such reporting;
record keeping and archiving for ICSRs;
periodic safety update reports (PSURs), (as applicable):
completeness and accuracy of the data included, appropriateness of decisions concerning data
that are not included;
addressing safety topics, providing relevant analyses and actions;
formatting according to requirements;
timeliness of submissions;
ongoing safety evaluation;
use of all relevant sources of information for signal detection;
appropriately applied methodology concerning analysis;
appropriateness of investigations and follow-up actions, e.g. the implementation of
recommendations following data review;
implementation of the RMP, or other commitments, e.g. conditions of marketing authorisation;
timely identification and provision of complete and accurate data to the competent
authority(ies), in particular in response to specific requests for data;
implementation of approved changes to safety communications and product information,
including internal distribution and external publication;
interventional (where appropriate) and non-interventional clinical trials:
reporting suspected unexpected serious adverse reactions (SUSARs) according to Directive
2001/20/EC and non-interventional study cases according to Directive 2001/83/EC;
receiving, recording and assessing cases from interventional and non-interventional trials (see
ICSRs);
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submission of study results and relevant safety information (e.g. development safety update
reports (DSURs) and information included in PSURs), where applicable, PASS or post-
authorisation efficacy studies (PAES) submissions, particularly when associated with specific
obligations or RMP commitments;
appropriate selection of reference safety information, maintenance of investigator brochures
and patient information with respect to safety;
the inclusion of study data in ongoing safety evaluation;
pharmacovigilance system:
QPPV roles and responsibilities, e.g. access to the quality system, the pharmacovigilance
system master file, performance metrics, audit and inspection reports, and their ability to take
action to improve compliance;
the roles and responsibilities of the marketing authorisation holder in relation to the
pharmacovigilance system;
accuracy, completeness and maintenance of the pharmacovigilance system master file;
quality and adequacy of training, qualifications and experience of staff;
coverage and adherence to the quality system in relation to pharmacovigilance, including
quality control and quality assurance processes;
fitness for purpose of computerised systems;
contracts and agreements with all relevant parties appropriately reflect responsibilities and
activities in the fulfilment of pharmacovigilance, and are adhered to.
The inspection may include the system for the fulfilment of conditions of a marketing authorisation and
the implementation of risk–minimisation activities, as they relate to any of the above safety topics.
III.B.4.2. For cause inspections
The scope of the inspection will depend on the specific trigger(s). Some, but not all of the elements
listed in III.B.4.1 and below, may be relevant:
QPPV involvement and awareness of product-specific issues;
in-depth examination of processes, decision-making, communications and actions relating to a
specific trigger and/or product.
III.B.4.3. Re-inspections
For the scope of a re-inspection, the following aspects should be considered:
review of the status of the system and/or corrective and preventive action plan(s) resulting
from previous pharmacovigilance inspection(s);
review of significant changes that have been made to the pharmacovigilance system since the
last pharmacovigilance inspection (e.g. change in the pharmacovigilance database, company
mergers or acquisitions, significant changes in contracted activities, change in QPPV);
review of process and/or product-specific issues identified from the assessment of information
provided by the marketing authorisation holder, or not covered in a prior inspection.
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The scope of re-inspection will depend on inspection history. It may be appropriate to conduct a
complete system review, for example if a long time has elapsed since the previous inspection, in which
case the elements listed in III.B.4.1. may be considered for the inspection scope, as appropriate.
III.B.5. Inspection process
Pharmacovigilance inspections should be planned, coordinated, conducted, reported on, followed-up
and documented in accordance with inspection procedures consistent with agreed Union
pharmacovigilance inspection procedures developed by the PhVIWG to support harmonisation for the
mutual recognition of pharmacovigilance inspections within the EU. These Union procedures will be
published as appendices to this Module. Improvement and harmonisation of inspection conduct will be
promoted by agreed processes and procedures, joint inspection(s) and sharing of experience and
training by national competent authority inspectorates.
The Union procedures on pharmacovigilance inspections will cover, at least, the following processes:
sharing of information;
inspection planning;
pre-authorisation inspections;
coordination of pharmacovigilance inspections in the EU;
coordination of third country inspections (including inspections of contractors in third countries);
preparation of pharmacovigilance inspections;
conduct of pharmacovigilance inspections;
reporting of pharmacovigilance inspections and inspection follow-up;
communication and prioritisation of pharmacovigilance inspections and findings;
interaction with PRAC in relation to inspections and their follow-up;
record-keeping and archiving of documents obtained or resulting from pharmacovigilance
inspections;
unannounced inspections;
sanctions and enforcement in case of serious non-compliance;
recommendations on the training and experience of inspectors performing pharmacovigilance
inspections.
These procedures will be revised and updated as deemed necessary. New procedures may also be
developed when the need is identified in relation to the inspection process.
III.B.6. Inspection follow-up
When non-compliance with pharmacovigilance obligations is identified during an inspection, follow-up
will be required until a corrective and preventive action plan is completed. The following follow-up
actions should be considered, as appropriate:
review of the marketing authorisation holder’s corrective and preventive action plan;
review of the periodic progress reports, when deemed necessary;
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re-inspection to assess appropriate implementation of the corrective and preventive action plan;
requests for submission of previously un-submitted data; submission of variations, e.g. to amend
product information; submission of impact analyses, e.g. following review of data that were not
previously considered during routine signal detection activities;
requests for issuing safety communications, including amendments of marketing and/or advertising
information;
requests for a meeting with the marketing authorisation holder to discuss the deficiencies, the
impact of the deficiencies and action plans;
communication of the inspection findings to other regulatory authorities (including outside the EU);
other product-related actions depending on the impact of the deficiencies and the outcome of
follow-up actions (this may include recalls or actions relating to the marketing authorisations or
clinical trial authorisations).
Sharing information and communication between inspectors and assessors is important for the proper
follow-up of inspections. Details of the processes relating to interaction between inspectors and
assessors and inspection follow-up will be elaborated further in the compilation of Union procedures on
pharmacovigilance inspections mentioned in III.B.5.
III.B.7. Regulatory actions and sanctions
Under EU legislation, in order to protect public health, competent authorities are obliged to ensure
compliance with pharmacovigilance obligations. When non-compliance with pharmacovigilance
obligations is detected, the necessary action will be judged on a case-by-case basis. What action is
taken will depend on the potential negative public health impact of the non-compliance(s), but any
instance of non-compliance may be considered for enforcement action. Action may be taken by the
Agency, the Commission or the competent authorities of the Member States as appropriate. As stated
in Article 111(8) of Directive 2001/83/EC, where appropriate, the Member State concerned shall take
the necessary measures to ensure that a marketing authorisation holder is subject to effective,
proportionate and dissuasive penalties. Moreover Regulation (EC) No 658/2007 also empowers the
Commission, to impose financial penalties on the holders of marketing authorisations to ensure the
enforcement of certain obligations connected with marketing authorisations for medicinal products
granted in accordance with Regulation (EC) No 726/2004.
In the event of non-compliance, possible regulatory options include the following, in accordance with
guidance and, as applicable, rules set in legislation:
education and facilitation: national competent authorities may communicate with marketing
authorisation holder representatives (e.g. in a meeting) to summarise the identified non-
compliances, to clarify the legal requirements and the expectations of the regulator, and to review
the marketing authorisation holder’s proposals for corrective and preventive actions;
provision of information to other competent authorities, the Agency or third country regulators
under the framework of confidentiality arrangements;
inspection: non-compliant marketing authorisation holders may be inspected to determine the
extent of non-compliance and then re-inspected to ensure compliance is achieved;
warning letter, non-compliance statement or infringement notice: these are non-statutory or
statutory instruments in accordance with national legislation which competent authorities may
issue stating the legislation and guideline that has been breached, reminding marketing
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authorisation holders of their pharmacovigilance obligations or specifying the steps that the
marketing authorisation holder must take and in what timeframe in order to rectify the non-
compliance and in order to prevent a further case of non-compliance;
competent authorities may consider making public a list of marketing authorisation holders found
to be seriously or persistently non-compliant;
actions against a marketing authorisation(s) or authorisation application(s) e.g.
Urgent Safety Restriction;
variation of the marketing authorisation;
suspension or revocation of the marketing authorisation;
delays in approvals of new marketing authorisation applications until corrective and preventive
actions have been implemented or the addition of safety conditions to new authorisations;
requests for pre-authorisation inspections;
product recalls e.g. where important safety warnings have been omitted from product information;
action relating to marketing or advertising information;
amendments or suspension of clinical trials due to product-specific safety issues;
administrative penalties, usually fixed fines or based on company profits or levied on a daily basis;
referral for criminal prosecution with the possibility of imprisonment (in accordance with national
legislation).
III.B.8. Record management and archiving
The principles and requirements to be followed will be described in the Union procedure on Record
Keeping and Archiving of Documents Obtained or Resulting from the Pharmacovigilance Inspections
referred to in III.B.5.
III.B.9. Qualification and training of inspectors
Inspectors who are involved in the conduct of pharmacovigilance inspections requested by their
Member States or by the CHMP should be officials of, or appointed by, the Member State in accordance
with national regulation and follow the provisions of the national competent authority.
It is recommended that inspectors are appointed based upon their experience and the minimum
requirements defined by the national competent authority. In addition, consideration should be given
to the recommendations for training and experience described in the compilation of Union procedures
on pharmacovigilance inspections mentioned in III.B.5.
The inspectors should undergo training to the extent necessary to ensure their competence in the skills
required for preparing, conducting and reporting inspections. They should also be trained in
pharmacovigilance processes and requirements in such way that they are able, if not acquired by their
experience, to comprehend the different aspects of a pharmacovigilance system.
Documented processes should be in place in order to ensure that inspection competencies are
maintained. In particular, inspectors should be kept updated with the current status of
pharmacovigilance legislation and guidance.
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Training and experience should be documented individually and evaluated according to the
requirements of the applicable quality system of the concerned competent authority.
III.B.10. Quality management of pharmacovigilance inspection process
Quality of the pharmacovigilance inspection process is managed by the national competent authorities
and covered by their pharmacovigilance systems and associated quality systems, meaning that the
process is also subject to audit. Guidance on establishment and maintenance of a quality assured
pharmacovigilance system is provided in Module I.
Quality and consistency of the inspections is facilitated by the Union procedures for pharmacovigilance
inspections developed by the PhVIWG to support the mutual recognition of inspections within the EU
mentioned in III.B.5.
III.C. Operation of the EU network
III.C.1. Sharing of information
The Agency and the Member States shall cooperate to facilitate the exchange of information on
inspections and in particular:
Information on inspections planned and conducted in order to avoid unnecessary repetition and
duplication of activities in the EU and optimise the inspection resources.
Information on the scope of the inspection in order to focus future inspections.
Information on the outcome of the inspection, in particular when the outcome is that the marketing
authorisation holder does not comply with the requirements laid down in legislation and relevant
guidance. A summary of the critical and/or major findings and a summary of the corresponding
corrective and preventive actions with their follow-up(s) should be exchanged.
Tools and procedures will be developed at EU level to facilitate and optimise the exchange and sharing
of information and the communication across the Union.
III.C.2. Role of the European Medicines Agency
III.C.2.1. General Role of the Agency
Regarding the monitoring of compliance with regulatory pharmacovigilance obligations and
pharmacovigilance inspections, the roles of the Agency are set out in Article 57(1)(c) and Article
57(1)(i) of Regulation (EC) No 726/2004 and can be summarised as follows:
Coordination of the monitoring of medicinal products for human use which have been authorised
within the Union, in particular by coordinating the evaluation and implementation of
pharmacovigilance obligations and systems and the monitoring of such implementation;
Coordination of the verification of compliance with pharmacovigilance obligations.
Pharmacovigilance inspections coordinated by the Agency are performed by the supervisory authority
concerned as outlined in III.C.3.2. The supervisory authority may be assisted by other national
competent authorities, when required.
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As part of this coordination role the Agency is responsible for:
establishing and maintaining processes through the PhVIWG to support the consistency and quality
of pharmacovigilance inspections of marketing authorisation holders with centrally authorised
products conducted by inspectorates of the national competent authorities;
coordinating and ensuring the implementation of a risk-based programme for routine
pharmacovigilance inspections of marketing authorisation holders with centrally authorised
products (see III.B.2) enabling the timely sharing of information on planned and conducted
pharmacovigilance inspections between Member States, with the aim of reducing duplication of
inspection activity and facilitating mutual recognition of inspection findings;
coordinating “for cause” inspections, as requested by the CHMP. If a “for cause” inspection has
been or will be conducted in a similar timeframe as a routine one, it may replace the need for the
planned routine inspection and the programme shall be revised to reflect this;
coordinating third country inspections: according to Article 111(1) of the Directive 2001/83/EC, the
Agency shall cooperate in the coordination of inspections in third countries. Member States should
liaise with the Agency when the need for an inspection of a third country site is identified in order
to ensure productive use of pharmacovigilance inspection resource in the interests of the Union;
communication and follow-up of inspections of Union interest across the Agency, the PRAC, the
CHMP, the CMD(h), the European network and with third country regulators, whenever
confidentiality arrangements are in place to facilitate this.
III.C.2.2. Role of the PRAC
The PRAC may make recommendations on the need and scope of "for cause" pharmacovigilance
inspections related to medicinal products of Union interest.
The PRAC may, in relation to issues of Union interest and where considered appropriate, review the
outcome of pharmacovigilance inspections and assess marketing authorisation holder-related
corrective and preventive action plan submission(s) in order to make or endorse further
recommendations on actions to be taken and their follow-up.
The PRAC is also responsible for providing input in the preparation of and agreeing on the risk-based
programme for routine pharmacovigilance inspections of marketing authorisation holders with centrally
authorised products outlined in III.B.2 and III.C.3.3.
III.C.2.3. Role of the CHMP
The CHMP is responsible for the request of pharmacovigilance inspections in the context of the
centralised procedure and for the endorsement of the recommendations made by the PRAC in relation
to the outcome of these inspections and their follow-up. The CHMP is also responsible for the adoption
of the risk-based programme for routine pharmacovigilance inspections outlined in III.B.2 and
III.C.3.3.
III.C.3. Role of the Commission
For medicinal products authorised under Regulation (EC) No 726/2004, the Commission may request
at any point in time the Agency to coordinate the conduct of a pharmacovigilance inspection if public
health information in the possession of the Commission so mandates.
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III.C.4. Role of the Member States
III.C.4.1. General Considerations
Member States should establish the legal and administrative framework within which
pharmacovigilance inspections operate, including the definition of the rights of inspectors for inspecting
pharmacovigilance sites and access to pharmacovigilance data.
Member States should provide sufficient resources and appoint adequately qualified inspectors to
ensure effective determination of compliance with good pharmacovigilance practice. The inspector(s)
appointed may be accompanied, when needed, by expert(s) on relevant areas. A Member State may
also request assistance from another Member State, in which case, access to the inspection sites and
data by the Member State providing assistance is desirable.
Pharmacovigilance inspections should be planned, coordinated, conducted, reported on, followed-up
and documented in accordance with inspection procedures consistent with agreed Union
pharmacovigilance inspection procedures developed by the PhVIWG to support harmonisation for the
mutual recognition of pharmacovigilance inspections within the EU as mentioned in section III.B.5.
The scheduling and conduct of these inspections will be driven by the preparation of inspection
programmes based on a systematic and risk-based approach as outlined in III.B.2 and III.C.3.3.
The national competent authorities, when preparing inspection programmes, should verify the
inspection status of the marketing authorisation holders they plan to inspect by considering the
information shared on planned or conducted inspections under the programmes in other Member
States in order to assure coordination of inspection activities, prevent unnecessary duplication and to
make the most efficient use of inspection resources.
When the pharmacovigilance system a national competent authority plans to inspect is the same as
that already inspected by another national competent authority, sharing of information on the scope
and outcomes of previous inspections and consideration of the national supervisory requirements, can
help to define the objective, scope and timing of that national inspection.
A common repository, accessible to all Member States, the Agency and the Commission, should be
created to facilitate this information sharing on pharmacovigilance inspections.
III.C.4.2. Role of the Supervisory Authority
The concept of the supervisory authority applies only in relation to centrally authorised products.
According to Article 18 of Regulation (EC) 726/2004, the supervisory authority for the conduct of
pharmacovigilance inspections shall be the competent authority of the Member State in which the
pharmacovigilance system master file is located.
The supervisory authorities for pharmacovigilance are responsible for verifying on behalf of the Union
that the marketing authorisation holder for the medicinal product satisfies the pharmacovigilance
requirements laid down in Directive 2001/83/EC and Regulation 726/2004/EC. They may, if this is
considered necessary, conduct pre-authorisation inspections to verify the accuracy and successful
implementation of the existing or proposed pharmacovigilance system [REG Art 19].
Where the sites selected to be inspected are located outside the EU, the same supervisory authority as
above will be responsible for the inspection on behalf of the Union. Where relevant or on request, and
in particular for product-specific issues, the inspection may be conducted or assisted by inspector(s)
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from the Rapporteur or Co-Rapporteur Member State and/or expert(s) from the Rapporteur or Co-
Rapporteur Member State or from other Member States as appropriate.
III.C.4.3. Inspection Programmes
A programme for routine inspections for centrally authorised products will be determined by the
Agency in conjunction with the supervisory authorities of the Member States, the PhVIWG, the PRAC
and the CHMP. These inspections will be prioritised based on the potential risk to public health,
considering the factors listed in III.B.5. As a general approach, a marketing authorisation holder
should be inspected on the basis of risk-based considerations, but at least once every 4 years.
If the same pharmacovigilance system is used for a variety of authorisation types (centralised and
national, mutual recognition and decentralised), then the results of a supervisory authority inspection
may be applicable for all products covered by that system.
This routine inspection programme will be separate from any “for cause” inspections, but if a “for
cause” inspection takes place it may replace the need for one under this programme, dependent on its
scope.
Member States are also responsible for the planning and coordination of pharmacovigilance inspections
within their territory in relation to products authorised nationally or via the mutual recognition or
decentralised procedures in order to ensure compliance with the legislation within their own Member
States and to verify the effectiveness of the marketing authorisation holder’s pharmacovigilance
system at national level.
As indicated in III.C.3.1, based on the information from other inspections, the national competent
authority will prioritise the inspections in its national programme and will use the information for the
preparation of an appropriate scope for the national inspection. For example, national competent
authorities may seek to verify the fulfilment of requirements concerning the national implementation of
specific risk-minimisation measures, national communications concerning safety, locally conducted
safety studies, or issues linked to national health care systems. A broader examination of
pharmacovigilance applied to particular products of national interest may also be appropriate if this
was not covered within the scope of a supervisory authority inspection.
III.C.5. Role of the Marketing Authorisation Holders and Applicants
Marketing authorisation holders with authorised products and applicants who have submitted new
applications under the centralised procedure are subject to pharmacovigilance inspections (see
III.B.1). Therefore both have responsibilities in relation to inspections, including but not limited to the
following:
Always to be inspection-ready as inspections may be unannounced.
To maintain and make available to the inspectors on request, no later than 7 calendar days after
the receipt of a request, the pharmacovigilance system master file as required by Article 23(4) of
Directive 2001/83/EC and Article 16(4) of Regulation (EU) 726/2004.
To ensure that the sites selected for inspection, which may include firms employed by the
marketing authorisation holder to perform pharmacovigilance activities, agree to be inspected
before the inspection is performed.
To make available to the inspectors any information and/or documentation required for the
preparation of the inspection within the deadline given or during the conduct of the inspection.
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To ensure that relevant staff involved in pharmacovigilance activities or related activities are
present and available during the inspection for interviews or clarification of issues identified.
To ensure that relevant pharmacovigilance data is accessible from at least one point in the Union
[DIR Art 107(1)].
To ensure that appropriate and timely corrective and preventive action plans are implemented to
address findings observed during an inspection, with appropriate prioritisation of critical and/or
major findings.
III.C.6. Inspection Fees
For inspections requested by the CHMP, an inspection fee(s) (and inspectors’ expenses where
applicable) will be charged in accordance with the Council Regulation (EC) No 297/95 on fees payable
to the European Agency for the Evaluation of Medicinal Products as amended and implementing rules
applicable at the time. For pharmacovigilance inspections performed in the context of national, mutual
recognition and decentralised procedures similar fees may or may not apply depending on the legal
requirements of the Member State carrying out the inspection.
III.C.7. Transparency
Information on the conduct and outcome of pharmacovigilance inspections and their follow-up may be
made publicly available . This will then be elaborated further in the compilation of Union procedures on
pharmacovigilance inspections mentioned in III.B.5.
29.07.2014
Datei
PD
See websites for contact details
European Medicines Agency www.ema.europa.eu
Heads of Medicines Agencies www.hma.eu
The European Medicines Agency is
an agency of the European Union
© European Medicines Agency and Heads of Medicines Agencies, 2014.
Reproduction is authorised provided the source is acknowledged.
15 April 2014
EMA/838713/2011 Rev 1*
Guideline on good pharmacovigilance practices (GVP)
Module V – Risk management systems (Rev 1)
Draft finalised by the Agency in collaboration with Member States and
submitted to ERMS FG
19 January 2012
Draft agreed by ERMS FG 24 January 2012
Draft adopted by Executive Director 20 February 2012
Released for public consultation 21 February 2012
End of consultation (deadline for comments) 18 April 2012
Revised draft finalised by the Agency in collaboration with Member
States
20 June 2012
Revised draft agreed by ERMS FG 21 June 2012
Revised draft adopted by Executive Director 22 June 2012
Anticipated date for coming into effect after finalisation 2 July 2012
Draft Revision 1* finalised by the Agency in collaboration with Member
States
12 March 2014
Draft Revision 1 provided to ERMS FG 2 April 2014
Draft Revision 1 adopted by Executive Director as final 15 April 2014
Date for coming into effect of Revision 1 28 April 2014
*Note: Revision 1 contains the following:
- Amendments to the definitions of Missing information and Safety concern in V.B.1. and subsequent
amendments of terms throughout the Module and in particular in V.B.8.9.;
- Amendment to the definition of Risk minimisation activity;
- Amendments to V.B.12. regarding part VI of the RMP (already implemented in published RMP
templates for MAHs);
- Amendments to V.C.4 and V.C.5. as regards requirements for variation applications;
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- Updates with regard to references to and implementation of legislation in V.A., V.B.2., V.B.5.,
V.B.9.2.1.c., V.B.10. and V.B.11.2.;
- Clarified wording in V.B.11.2.;
- Editorial improvements throughout the Module without impact on its content.
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Table of contents
V.A. Introduction ......................................................................................... 6
V.B. Structures and processes ..................................................................... 7
V.B.1. Terminology ..................................................................................................... 7
V.B.2. Principles of risk management ............................................................................ 8
V.B.3. Responsibilities for risk management within an organisation ................................. 10
V.B.3.1. Marketing authorisation holders and applicants ................................................ 10
V.B.3.2. Competent authorities ................................................................................... 10
V.B.4. Objectives of a risk management plan ............................................................... 11
V.B.5. Structure of the risk management plan .............................................................. 12
V.B.6. Detailed description of each part of the risk management plan .............................. 14
V.B.7. RMP part I “Product overview” .......................................................................... 14
V.B.8. RMP part II “Safety specification” ...................................................................... 16
V.B.8.1. RMP module SI “Epidemiology of the indications and target population” .............. 17
V.B.8.2. RMP module SII “Non-clinical part of the safety specification” ............................ 17
V.B.8.3. RMP module SIII “Clinical trial exposure” ......................................................... 17
V.B.8.4. RMP module SIV “Populations not studied in clinical trials” ................................. 18
V.B.8.5. RMP module SV “Post-authorisation experience” ............................................... 20
V.B.8.5.1. RMP module SV section “Action taken by regulatory authorities and/or marketing
authorisation holders for safety reasons” ..................................................................... 21
V.B.8.5.2. RMP module SV section “Non-study post-authorisation exposure” .................... 21
V.B.8.5.3. RMP module SV section “Post-authorisation use in populations not studied in
clinical trials” ............................................................................................................ 22
V.B.8.5.4. RMP module SV section “Post-authorisation off-label use” ............................... 22
V.B.8.5.5. RMP module SV section “Epidemiological study exposure” ............................... 22
V.B.8.6. RMP module SVI “Additional EU requirements for the safety specification” ........... 22
V.B.8.6.1. RMP module SVI section “Potential for harm from overdose” ........................... 23
V.B.8.6.2. RMP module SVI section “Potential for transmission of infectious agents” .......... 23
V.B.8.6.3. RMP module SVI section “Potential for misuse for illegal purposes” .................. 23
V.B.8.6.4. RMP module SVI section “Potential for medication errors” ............................... 23
V.B.8.6.5. RMP module SVI section “Potential for off-label use” ...................................... 24
V.B.8.6.6. RMP module SVI section “Specific paediatric issues” ....................................... 25
V.B.8.7. RMP module SVII “Identified and potential risks” .............................................. 25
V.B.8.7.1. RMP module SVII section “Newly identified safety concerns” ........................... 25
V.B.8.7.2. RMP module SVII section “Recent study reports with implications for safety
concerns”................................................................................................................. 26
V.B.8.7.3. RMP module SVII section “Details of important identified and potential risks from
clinical development and post-authorisation experience” ................................................ 26
V.B.8.7.4. RMP module SVII section “Identified and potential interactions including food-drug
and drug-drug interactions” ....................................................................................... 28
V.B.8.7.5. RMP module SVII section “Pharmacological class effects” ................................ 28
V.B.8.8. RMP module SVII “Identified and potential risks (ATMP version)” ........................ 28
V.B.8.8.1. RMP module SVII section “Newly identified safety concerns (ATMP)” ................ 28
V.B.8.8.2. RMP module SVII section “Recent study reports with implications for safety
concerns (ATMP)” ..................................................................................................... 29
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V.B.8.8.3. RMP module SVII section “Details of important identified and potential risks
(ATMP)” ................................................................................................................... 29
V.B.8.9. RMP module SVIII “Summary of the safety concerns” ....................................... 31
V.B.9. RMP Part III “Pharmacovigilance plan” ............................................................... 31
V.B.9.1. RMP part III section “Routine pharmacovigilance activities” ............................... 32
V.B.9.2. RMP part III section “Additional pharmacovigilance activities” ............................ 33
V.B.9.2.1. Particular situations with post authorisation safety studies .............................. 34
V.B.9.3. RMP part III section “Action plans for safety concerns with additional
pharmacovigilance requirements” ............................................................................... 35
V.B.9.4. RMP part III section “Summary table of additional pharmacovigilance activities” .. 36
V.B.10. RMP part IV “Plans for post-authorisation efficacy studies” .................................. 38
V.B.10.1. RMP part IV section “Summary of existing efficacy data” ................................. 38
V.B.10.2 Tables of post-authorisation efficacy studies ................................................... 39
V.B.11. RMP Part V “Risk minimisation measures” ......................................................... 40
V.B.11.1. RMP part V section “Routine risk minimisation” ............................................... 41
V.B.11.2. RMP part V section “Additional risk minimisation activities” .............................. 43
V.B.11.3. Format of risk minimisation plan(s) ............................................................... 44
V.B.11.4. RMP part V section “Evaluation of the effectiveness of risk minimisation activities”
.............................................................................................................................. 44
V.B.11.5. RMP part V section “Summary of risk minimisation measures” .......................... 45
V.B.12. RMP part VI “Summary of activities in the risk management plan by medicinal
product” .................................................................................................................. 45
V.B.12.1. RMP part VI section “format and content of the summary of the RMP” ............... 46
V.B.12.2. RMP part VI section “Overview of disease epidemiology“ .................................. 46
V.B.12.3. RMP part VI section “Summary of treatment benefits “ .................................... 46
V.B.12.4. RMP part VI section “Unknowns relating to treatment benefits” ........................ 46
V.B.12.5. RMP part VI section “Summary of safety concerns” ......................................... 47
V.B.12.6. RMP part VI section “Summary of risk minimisation activities by safety concern” 48
V.B.12.7. RMP part VI section “Planned post-authorisation development plan” .................. 48
V.B.12.8. RMP part VI section “Summary of changes to the risk management plan over time”
.............................................................................................................................. 49
V.B.13. RMP part VII “Annexes to the risk management” ............................................... 49
V.B.14. The relationship between the risk management plan and the periodic safety update
report ...................................................................................................................... 50
V.B.14.1. Common modules between periodic safety update report and risk management
plan ........................................................................................................................ 50
V.B.15. Principles for assessment of risk management plans .......................................... 51
V.B.16. Quality systems and record management ......................................................... 53
V.C. Operation of the EU network .............................................................. 53
V.C.1. Legal basis for the implementation of risk management within the EU ................... 53
V.C.2. Risk management in the EU .............................................................................. 54
V.C.3. Situations when a risk management plan should be submitted .............................. 54
V.C.3.1. Requirements in specific situations ................................................................. 55
V.C.4. Submission of the risk management plan ........................................................... 57
V.C.5. Updates to the risk management plan ................................................................ 57
V.C.5.1. Updates to the risk management plan submitted during a procedure .................. 58
V.C.6. Procedure for the assessment of the risk management plan within the EU .............. 59
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V.C.7. Implementation of additional risk minimisation activities for centrally authorised
products .................................................................................................................. 59
V.C.8. Transparency .................................................................................................. 60
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V.A. Introduction
It is recognised that at the time of authorisation, information on the safety of a medicinal product is
relatively limited. This is due to many factors including the relatively small numbers of subjects in
clinical trials compared with the intended treatment population, restricted population in terms of age,
gender and ethnicity, restricted co-morbidity, restricted co-medication, restricted conditions of use,
relatively short duration of exposure and follow up, and the statistical problems associated with looking
at multiple outcomes.
A medicinal product is authorised on the basis that in the specified indication(s), at the time of
authorisation, the risk-benefit balance is judged to be positive for the target population. A typical
medicinal product will have multiple risks associated with it and individual risks will vary in terms of
severity, effect on individual patients and public health impact. However, not all actual or potential
risks will have been identified at the time when an initial authorisation is sought and many of the risks
associated with the use of a medicinal product will only be discovered and characterised post-
authorisation. Planning of the necessary pharmacovigilance activities to characterise the safety profile
of the medicinal product will be improved if it is more closely based on specific issues identified from
pre- or post-authorisation data and from pharmacological principles.
However, the purpose of risk identification and characterisation is to allow for risk minimisation or
mitigation wherever possible. Therefore risk management has three stages which are inter-related and
re-iterative:
1. characterisation of the safety profile of the medicinal product including what is known and not
known;
2. planning of pharmacovigilance activities to characterise risks and identify new risks and increase
the knowledge in general about the safety profile of the medicinal product;
3. planning and implementation of risk minimisation and mitigation and assessment of the
effectiveness of these activities.
The chapter on risk management systems for medicinal products for human use in Volume 9A, which
this guidance replaces, was based solely on managing risks. However, when considering how to
maximise, or indeed assess, the risk-benefit balance, risks need to be understood in the context of
benefit. In assessing the risk-benefit balance at the time of authorisation, the assumption is made that
these benefits and risks apply to the whole target population. However, there may be subsets of
patients for whom the risk is greater than that for the target population as a whole, or in whom the
benefit may not be as great. In addition, efficacy in the clinical trial setting may not reflect the true
effectiveness of the medicinal product in everyday medical practice and so the risk-benefit balance of a
medicinal product as assessed at the time of authorisation will inevitably change post-authorisation.
Regulation (EC) No 726/2004 and Directive 2001/83/EC include provisions for both post-authorisation
safety studies and post-authorisation efficacy studies to be a condition of the marketing authorisation
in certain circumstances [REG Art 9(4), Art 10a(1), DIR Art 21a, Art 22a(1)] and for these studies to
be included in the risk management plan (RMP) [DIR Art 22c].
Risk management is a global activity. However, because of differences in indication and healthcare
systems, target populations may be different across the world and risk minimisation activities will need
to be tailored to the system in place in a particular country or global region. In addition, differences in
disease prevalence and severity, for example, may mean that the benefits of a medicinal product may
also vary between regions. Therefore a product may have different versions of a RMP for each region
although there will be core elements which are common to all. For example much of the safety
specification will be the same regardless of where the medicinal product is being used but the
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epidemiology of the disease may vary between e.g. Africa and Europe, and there may be additional or
fewer safety concerns depending upon the target population and indication,
The move to a modular format of the risk management plan (RMP) came into force in July 2012 and
should facilitate submission to different regulatory authorities. . Guidance on templates and submission
of RMPs is kept up-to-date on the Agency’s website1 (see Annex II Related links).
Risk management, is applicable to medicinal products at any point in their lifecycle. However, this
module concentrates on peri- and post-authorisation risk management and is applicable to all products
regardless of the procedure (centralised, decentralised, mutual recognition or national) leading to
authorisation in the EU.
The risks addressed in this guidance are those related to non-clinical and clinical safety. In addition,
quality issues may be relevant if they impact on the safety and/or efficacy of the product. Where the
disposal of the product might pose a particular risk because of remaining active substance (e.g.
patches) this should also be addressed.
Although this module includes the principles of risk minimisation, and details of routine risk
minimisation measures, more detail on, in particular, additional risk minimisation tools and the
measurement of the effectiveness of risk management can be found in Module XVI.
V.B. Structures and processes
V.B.1. Terminology
Identified risk
An untoward occurrence for which there is adequate evidence of an association with the medicinal
product of interest. Examples include:
• an adverse reaction adequately demonstrated in non-clinical studies and confirmed by clinical data;
• an adverse reaction observed in well-designed clinical trials or epidemiological studies for which the
magnitude of the difference compared with the comparator group, on a parameter of interest
suggests a causal relationship;
• an adverse reaction suggested by a number of well-documented spontaneous reports where
causality is strongly supported by temporal relationship and biological plausibility, such as
anaphylactic reactions or application site reactions.
In a clinical trial, the comparator may be placebo, active substance or non-exposure.
Potential risk
An untoward occurrence for which there is some basis for suspicion of an association with the
medicinal product of interest but where this association has not been confirmed. Examples include:
• toxicological findings seen in non-clinical safety studies which have not been observed or resolved
in clinical studies;
• adverse events observed in clinical trials or epidemiological studies for which the magnitude of the
difference, compared with the comparator group (placebo or active substance, or unexposed
group), on a parameter of interest raises a suspicion of an association, but is not large enough to
suggest a causal relationship;
1 www.ema.europa.eu
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• a signal arising from a spontaneous adverse reaction reporting system;
• an event known to be associated with other active substances within the same class or which could
be expected to occur based on the properties of the medicinal product.
Missing information
Gaps in knowledge about a medicinal product, related to safety or use in particular patient populations,
which could be clinically significant.
Examples of missing information include populations not studied (e.g. pregnant women or patients
with severe renal impairment) or where there is a high likelihood of off-label use.
Important identified risk and important potential risk
An identified risk or potential risk that could have an impact on the risk-benefit balance of the product
or have implications for public health.
What constitutes an important risk will depend upon several factors, including the impact on the
individual, the seriousness of the risk, and the impact on public health. Normally, any risk that is likely
to be included in the contraindications or warnings and precautions section of the product information
should be considered important.
Risk management system
A set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or
minimise risks relating to medicinal products including the assessment of the effectiveness of those
activities and interventions [DIR Art 1(28b)].
Risk management plan
A detailed description of the risk management system [DIR Art 1(28c)].
Risk minimisation activity (used synonymously with risk minimisation measure)
An intervention intended to prevent or reduce the probability of the occurrence of an adverse reaction
associated with the exposure to a medicine or to reduce its severity should it occur.
Safety concern
An important identified risk, important potential risk or missing information.
Target population (treatment)
The patients who might be treated with the medicinal product in accordance with the indication(s) and
contraindications in the authorised product information.
V.B.2. Principles of risk management
The overall aim of risk management is to ensure that the benefits of a particular medicinal product (or
a series of medicinal products) exceed the risks by the greatest achievable margin for the individual
patient and for the target population as a whole. This can be done either by increasing the benefits or
by reducing the risks. Although the primary aim and focus of the RMP remains that of risk
management, the evaluation of the need for efficacy studies (including those linked to the Safety
Specification section on Missing Information) and their integration, where necessary, in the RMP may
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enable resources to be used more efficiently and for risks to be put into context. The RMP therefore
includes the planning of such studies and is without prejudice to the specific efficacy guidance foreseen
in Article 108a of Directive 2001/83/EC.
The principles of risk management are the same regardless of stakeholder or territory (see below).
Figure V.1. The risk management cycle
RISK MANAGEMENTRISK MANAGEMENT
CYCLECYCLE
However, the actions and responsibilities within each step of the cycle will vary according to whether
the stakeholder is an applicant/marketing authorisation holder, competent authority, healthcare
professional or patient. Other players may be involved in risk-benefit management such as: patient
organisations, learned societies, health economists, health authorities, national safety organisations,
environmental advisors, occupational health professionals and pharmaceutical distributors but their
roles will usually be smaller and complementary to that of the main players.
For applicants/marketing authorisation holders and competent authorities in the EU, there is specific
mention of risk management in the legislation. In the EU, as well as complying with the legislation,
the primary document and process for risk management adheres to the principles in the International
Conference for Harmonisation (ICH) Guideline E2E on Pharmacovigilance Planning. Outside of the EU,
some territories may have local legislation enshrining either risk management in general or adopting
the specific ICH E2E guidance or have developed local guidance. For healthcare professionals, product
information, medical treatment guidelines and any materials produced by marketing authorisation
holders, competent authority or health authorities will direct prescribing, dispensing, treatment and
management of both benefit and risks. For patients, the majority of medicinal products will be
prescribed by doctors and dispensed by pharmacists so that management of benefits and risks will
primarily involve complying with treatment schedules and recommendations, being aware of important
risks and what actions to take, and reporting to their doctor, pharmacist, and national competent
authority any untoward effects. However, in some countries patients may buy medicines directly
without guidance from healthcare practitioners so will need to understand the potential benefits and
risks of the product and what measures they need to comply with to use the medicine safely and
effectively. Whatever the setting, patients who understand the potential benefits and risks of a
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medicinal product are better equipped to decide whether or not to be treated and to comply with
suggested risk minimisation activities.
V.B.3. Responsibilities for risk management within an organisation
The principle organisations directly involved in medicinal products’ risk management planning are
applicants/marketing authorisation holders and the competent authorities who regulate them. Within
the EU, responsibility for authorisation and supervision of medicinal products is shared between the
national competent authorities in Member States, the European Commission and the European
Medicines Agency, with the balance of responsibilities depending upon the route of authorisation.
V.B.3.1. Marketing authorisation holders and applicants
In relation to risk management of its medicinal products, an applicant/marketing authorisation holder
is responsible for:
• ensuring that it constantly monitors the risks of its medicinal products in compliance with relevant
legislation and reports the results of this, as required, to the appropriate competent authorities;
• taking all appropriate actions to minimise the risks of the medicinal product and maximise the
benefits including ensuring the accuracy of all information produced by the company in relation to
its medicinal products, and actively updating and promptly communicating it when new information
becomes available;
Other Modules within GVP deal with specific aspects of the above so this Module is confined to the risk
management plan and its contents.
ICH-E2E defines two basic parts of a RMP: the safety specification and the pharmacovigilance plan. It
does not include risk minimisation. However it was acknowledged at the time of development of ICH-
E2E that risk minimisation was an integral part of risk management planning. Details of how the safety
specification and pharmacovigilance plan are integrated within the RMP and the detailed structure and
format are provided in V.B.5 to V.B.7.
Producing a RMP requires the input of different specialists and departments within and/or outside an
organisation. The safety specification may require involvement of toxicologists, clinical
pharmacologists, clinical research physicians, pharmacoepidemiologists and pharmacovigilance
experts. The input required for the pharmacovigilance plan may require any of these experts
depending upon the safety concerns identified in the safety specification and the types of activities
planned to address them. The design of risk minimisation activities should involve people with
expertise in communication and, where appropriate, patients and/or healthcare professionals. Since a
risk management plan is primarily a pharmacovigilance document, ideally the production of it should
be managed by personnel with appropriate pharmacovigilance training in either the pharmacovigilance
or regulatory departments, depending upon company structure. Regardless of who prepares the RMP,
the responsibility for the content and accuracy of the RMP remains with the marketing authorisation
applicant/holder who should ensure oversight by someone with the appropriate scientific background
within the company.
Further guidance on individual risk minimisation activities is provided in Module XVI.
V.B.3.2. Competent authorities
The general responsibilities of competent authorities are discussed in Module I. In relation to risk
management, the principal responsibilities of competent authorities are:
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• constantly monitoring the benefits and risks of medicinal products including assessing the reports
submitted by pharmaceutical companies, healthcare professionals, patients and, where
appropriate, other sources of information;
• taking appropriate regulatory actions to minimise the risks of the medicinal product and maximise
the benefits including ensuring the accuracy and completeness of all information produced by the
company in relation to its medicinal products;
• ensuring the implementation of risk minimisation activities at a national level;
• effectively communicating with stakeholders when new information becomes available. This
includes providing information in an appropriate format to patients, healthcare physicians, patient
groups and learned societies;
• when necessary, ensuring that marketing authorisation holders of generic and/or similar biological
medicinal products make similar changes to their risk minimisation measures when changes are
made to those of the reference medicinal product;
• providing information to other regulatory authorities, this includes notification of any safety
activities in relation to a product, including changes to the product information of originator and/or
reference medicinal products.
Many of the associated tasks and activities are described elsewhere in GVP and in other scientific
guidances. One of the principle tasks of regulatory authorities in relation to risk management is the
assessment of risk management plans. The different parts of the RMP need different areas of expertise
so ideally assessment of risk management plans should be performed by a multi-disciplinary team.
How this can be achieved will depend upon the organisational structure of the competent authority but
could include multi-disciplinary meetings or pharmacovigilance experts reviewing RMPs alongside
expert assessment reports relating to different sections of the submitted dossier.
V.B.4. Objectives of a risk management plan
As per the Commission Implementing Regulation (EU) No 520/2012 [IR], the RMP must contain the
following elements which:
• identify or characterise the safety profile of the medicinal product(s) concerned;
• indicate how to characterise further the safety profile of the medicinal product(s) concerned;
• document measures to prevent or minimise the risks associated with the medicinal product
including an assessment of the effectiveness of those interventions;
• document post-authorisation obligations that have been imposed as a condition of the marketing
authorisation [IR Art 30].
There is an implicit requirement that to fulfil these obligations a RMP should also:
• describe what is known and not known about the safety profile of the concerned medicinal
product(s);
• indicate the level of certainty that efficacy shown in clinical trial populations will be seen when the
medicine is used in the wider target populations seen in everyday medical practice and document
the need for studies on efficacy in the post-authorisation phase (also known as effectiveness
studies);
• include a description of how the effectiveness of risk minimisation measures will be assessed.
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The RMP is a dynamic, stand-alone document which should be updated throughout the life-cycle of the
products. For products requiring periodic safety update reports (PSURs), certain (parts of) modules
may be used for both purposes (see V.B.14.).
V.B.5. Structure of the risk management plan
The RMP consists of seven parts. Certain parts of the RMP, in particular the safety specification, are
subdivided into modules [IR Annex 1] so the content can be tailored to the specifics of the medicinal
product and modules added/removed or re-used in other documents (e.g. PSURs). RMP part II
modules generally follow the section titles in the Safety Specification of ICH-E2E, whilst RMP part III
follows the Pharmacovigilance Plan. Differences between indications, formulations and target
populations, if several medicinal products have the same active substance, will be similarly
accommodated by dividing the relevant parts of the RMP into modules and/or sections. The modular
structure also means that the RMP can be updated easily. As the product matures, some RMP modules
or sections may cease changing – for example non clinical studies may stop at a certain time as may
clinical trials. These RMP modules can be effectively “locked” until new data needs to be added. In
addition, certain RMP modules may be omitted in specific circumstances (see V.C.3.1.).
The submitted RMP should follow the RMP template (see Annex II Related links). The amount of
information, particularly in RMP part II, which can be provided will depend on the type of medicinal
product and where it is in its lifecycle but this guidance provides an overview of the level of information
needed and its format.
The risk management system shall be proportionate to the identified risks and the potential risks of the
medicinal product, and the need for post-authorisation safety data [DIR Art 8(3)]. This proportionality
can be achieved in three ways: by reducing the number of modules which need to be submitted for
products meeting certain conditions (such as well-established products/generics see table V.3), and by
ensuring that requirements for post-authorisation studies and risk minimisation activities reflect the
important risks and important uncertainties of the product.
An overview of the parts and modules of the RMP is provided below [IR Annex I]:
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Figure V.2. Overview of the parts and modules of the RMP
Where a RMP concerns more than one medicinal product, a separate RMP part VI must be provided for
each medicinal product [IR Art 31].
Information should be provided in enough detail to enable an assessor to understand the issues being
presented. Unless specifically mentioned in this guidance, cross references to other parts of the dossier
should be avoided since it is intended that the RMP should be a largely stand-alone document that is a
scientific synopsis of the relevant parts of the dossier, emphasising the important clinically relevant
facts. To aid consistency between the information provided in the common technical document (CTD)
and the RMP, the table below indicates the location of information in the CTD is summarised for the
RMP:
Table V.1 Mapping between RMP modules and CTD
RMP CTD
Part I Active substance information Module 2.3 Quality overall
summary
Module 3 Quality
Module SI Epidemiology of the target population Module 2.5 Clinical overview
Module SII Non-clinical part of safety specification Module 2.4 Non-clinical overview
Module 2.6 Non-clinical written
and tabulated
summaries
Module 4 Non-clinical study
reports
Module SIII Clinical trial exposure Module 2.7 Clinical summary -
briefly
Module 5 Clinical Study reports
Module SIV Populations not studied in clinical trials Module 2.5 Clinical overview
Part I Product(s) overview
Part II Safety specification
Module SI Epidemiology of the indication(s) and target population(s)
Module SII Non-clinical part of the safety specification
Module SIII Clinical trial exposure
Module SIV Populations not studied in clinical trials
Module SV Post-authorisation experience
Module SVI Additional EU requirements for the safety specification
Module SVII Identified and potential risks
Module SVIII Summary of the safety concerns
Part III Pharmacovigilance plan
Part IV Plans for post-authorisation efficacy studies
Part V Risk minimisation measures (including evaluation of the effectiveness of risk minimisation
measures)
Part VI Summary of the risk management plan
Part VII Annexes
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RMP CTD
Module SV Post authorisation experience Module 2.5 Clinical overview -
briefly
Module SVII Identified and potential risks Module 2.5 Clinical overview
(including benefit
risk conclusion)
Module 2.7 Clinical summary
(SPC)
Module SVIII Summary of the safety concerns Module 2.5 Clinical overview
Module 2.7 Clinical summary
Part III Pharmacovigilance activities Module 2.5 Clinical overview
Module 2.7 Clinical summary
Part IV Plans for post authorisation efficacy studies (including
presentation of efficacy data)
Module 2.5 Clinical overview
Module 2.7 Clinical summary
Part V Risk minimisation measures Module 2.5 Clinical overview
Module 2.7 Clinical summary
Copies of literature referenced in the RMP should be included in RMP annex 12.
V.B.6. Detailed description of each part of the risk management plan
The description of the parts and modules of an RMP provide guidance on the main topics which should
be covered within each specific area. However, some sections may not be relevant to all medicinal
products and there may be additional topics which need to be included but are not mentioned. The
RMP is part of the scientific dossier of a product and as such should be scientifically based and not be
promotional.
Under Regulation (EC) No 1394/20072, certain products for human medicinal use are categorised
within the EU as advanced therapy medicinal products (ATMPs). These products are fully defined in the
above Regulation but broadly comprise:
• gene therapy medicinal products;
• somatic cell therapy medicinal products;
• tissue engineered products.
Because of the nature of these products, risks may occur which are not normally a consideration with
other medicinal products including risks to living donors, risks of germ line transformation and
transmission of vectors. For this reason, for ATMPs, RMP module VII Identified and potential risks
(ATMP) should replace RMP module VII Identified and potential risks as this provides greater flexibility
in consideration of the additional risks.
V.B.7. RMP part I “Product overview”
This should provide the administrative information on the RMP and an overview of the product(s)
covered within it.
The information should include:
2 Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy
medicinal products
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Active substance information:
• active substance(s);
• pharmacotherapeutic group(s) (ATC code);
• name of marketing authorisation holder or applicant;
• date and country of first authorisation worldwide (if applicable);
• date and country of first launch worldwide (if applicable);
• number of medicinal product(s) to which this RMP refers.
Administrative information on the RMP:
• data lock point of the current RMP;
• date submitted and the version number;
• list of all parts and modules of the RMP with date and version of the RMP when the part/module
was last (updated and) submitted.
and
for each medicinal product included in the RMP:
• authorisation procedure (central, mutual recognition, decentralised, national);
• invented name(s) in the European Economic Area (EEA);
• brief description of the product including:
− chemical class;
− summary of mode of action;
− important information about its composition (e.g. origin of active substance of biologicals,
relevant adjuvants or residues for vaccines);
• indications:
− current (if applicable) in the EEA;
− proposed (if applicable) in the EEA;
• dosage:
− current (if applicable) in the EEA;
− proposed (if applicable) in the EEA;
• pharmaceutical forms and strengths:
− current (if applicable) in the EEA ;
− proposed (if applicable) in the EEA;
• whether the product is the subject of additional monitoring in the EU.
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V.B.8. RMP part II “Safety specification”
The purpose of the safety specification is to provide a synopsis of the safety profile of the medicinal
product(s) and should include what is known and not known about the medicinal product(s). It should
be a summary of the important identified risks of a medicinal product, important potential risks, and
missing information. Missing information is defined as: gaps in knowledge about a medicinal product,
related to safety or use in particular patient populations, which could be clinically significant (see
Annex I). It should also address the populations potentially at risk (where the product is likely to be
used i.e. both labelled and off-labelled use), and outstanding safety questions which warrant further
investigation to refine understanding of the risk-benefit balance during the post-authorisation period.
In the RMP, the safety specification will form the basis of the pharmacovigilance plan, and the risk
minimisation plan.
The safety specification consists of eight RMP modules of which RMP modules SI-SV, SVII and SVIII
correspond to safety specification headings in ICH-E2E. RMP module SVI includes additional elements
required to be submitted in the EU.
Module SI Epidemiology of the indication(s) and target population(s)
Module SII Non-clinical part of the safety specification
Module SIII Clinical trial exposure
Module SIV Populations not studied in clinical trials
Module SV Post-authorisation experience
Module SVI Additional EU requirements for the safety specification
Module SVII Identified and potential risks
Module SVIII Summary of the safety concerns
RMP modules SIII–SV form the “Limitations of the human safety database” part of the ICH-E2E safety
specification and these, with the addition of RMP modules SI and SVII form the clinical part of the
safety specification. RMP modules SVI and the ATMP version of SVII are EU specific although the topics
may apply in any territory.
It is recommended that applicants/marketing authorisation holders follow the structure of elements
provided below when compiling the safety specification. The elements of the safety specification that
are included are only a guide. The safety specification can include additional elements, depending on
the nature of the product and its development programme. Elements which might need to be
incorporated include:
• quality aspects if relevant in relation to the safety and efficacy of the product;
• the disposal of the product where it might pose a particular risk because of remaining active
substance (e.g. patches);
• innovative pharmaceutical forms; or
• use with a medical device.
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V.B.8.1. RMP module SI “Epidemiology of the indications and target
population”
The epidemiology of the indication(s) should be discussed. This discussion should include incidence,
prevalence, mortality and relevant co-morbidity, and should whenever possible be stratified by age,
sex, and racial and/or ethnic origin. Differences in the epidemiology in the different regions should be
discussed, where feasible, (because the epidemiology of the indication(s) may vary across regions),
but the emphasis should be on the epidemiology in the EU of the proposed indication.
Information should be provided on the important co-morbidities in the target population. For example:
if a medicinal product is intended for treating prostate cancer, the target population is likely to be men
over the age of 50 years. Men over the age of 50 are also at risk of myocardial infarction. To identify
whether a medicinal product might be increasing the risk of myocardial infarction, it is important to
know how many cases would be expected amongst prostate cancer patients (ideally) or men in the
same age group, not taking the medicinal product. Estimation of the risk in the target population, as
compared with the same age/sex group in the general population may be particularly important if the
disease itself increases the risk of a particular adverse event.
The RMP should include a statement of the intended purpose and impact of the product e.g. whether it
is intended to prevent disease, to prevent particular serious outcomes due to a condition or to reduce
progression of a chronic disease.
V.B.8.2. RMP module SII “Non-clinical part of the safety specification”
This RMP module should present a summary of the important non-clinical safety findings, for example:
• toxicity (key issues identified from e.g. repeat-dose toxicity, reproductive/developmental toxicity,
nephrotoxicity, hepatotoxicity, genotoxicity, carcinogenicity);
• general pharmacology (e.g. cardiovascular, including QT interval prolongation, nervous system);
• drug interactions;
• other toxicity-related information or data.
What constitutes an important safety finding will depend upon the medicinal product, the target
population and experience with other similar compounds or therapies in the same class. Normally
significant areas of toxicity (by target organ system), and the relevance of the findings to the use in
humans, should be discussed. Also quality aspects if relevant to safety (e.g. important information on
the active substance or its impurities, e.g. genotoxic impurities) should be discussed. If a product is
intended for use in women of childbearing age, data on the reproductive/developmental toxicity should
be explicitly mentioned and the implications for use in this population discussed. Where the non-clinical
safety finding could constitute an important risk to the target population, it should be included as a
safety concern in RMP module SVIII.
For other special populations depending upon the indication and target population, consideration
should be given to whether specific non-clinical data needs exist.
V.B.8.3. RMP module SIII “Clinical trial exposure”
In order to assess the limitations of the human safety database, data on the patients studied in clinical
trials should be provided. This data should be provided in the most appropriate format, e.g.
tables/graphs. The size of the study population should be detailed using both numbers of patients and,
where appropriate, patient time (patient-years, patient-months) exposed to the medicinal product.
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This should be stratified for relevant categories and also by the type of trial (randomised blinded trial
population only and all clinical trial populations.) Stratifications would normally include:
• age and gender;
• indication;
• dose;
• racial origin (see also V.B.8.4.).
Duration of exposure should be provided either graphically by plotting numbers of patients against
time or in tabular format.
The exposure of special populations (pregnant women, breast-feeding women, renal impairment,
hepatic impairment, cardiac impairment, sub-populations with relevant genetic polymorphisms,
immuno-compromised) should be provided as appropriate. The degree of renal, hepatic or cardiac
impairment should be specified as well as the genetic polymorphism.
The categories above are only suggestions and tables/graphs should be tailored to the product. For
example, indication may not be a relevant stratification for a medicinal product where only one
indication has been studied, and route of administration, number of courses/immunisations or repeat
administrations may be important categories to be added.
When presenting age data, categories should be chosen which are relevant to the target population.
Broad artificial divisions which are not clinically relevant, such as <65 and >65, should be avoided.
Paediatric data should be divided by categories (e.g. ICH-E11); similarly the data on elderly patients
should be considered for stratification into categories such as 65-74, 75-84 and 85+, although the age
strata should reflect that of the target population. For teratogenic drugs, stratification into age
categories relating to childbearing potential might be appropriate for the female population.
Unless clearly relevant, data should not be presented by individual trial but should be pooled. Totals
should be provided for each table/graph as appropriate. Where patients have been enrolled in more
than one trial (e.g. open label extension study following a trial) they should only be included once in
the age/sex/ethnic origin tables. Where differences in the total numbers of patients arise between
tables, the tables should be annotated to reflect the reasons for discrepancy.
When the RMP is being submitted with an application for a new indication, a new pharmaceutical form
or route, the clinical trial data specific to the application should be presented separately at the start of
the module as well as being included in the summary tables (as described above) representing pooled
data across all indications.
V.B.8.4. RMP module SIV “Populations not studied in clinical trials”
RMP module SIV should discuss which sub-populations within the expected target population have not
been studied or have only been studied to a limited degree in the clinical trial population. Limitations of
the clinical trials should also be presented in terms of the relevance of inclusion and exclusion criteria
in relation to the target population. This is particularly important when exclusion criteria are not
proposed as contraindications for the drug. Lists of inclusion/exclusion criteria should not be provided
by trial, but a summary of the effect of these in the overall development programme in relation to the
target population should be provided. In discussing differences between target populations and those
exposed in clinical trials it should be noted that some differences may arise through trial setting (e.g.
hospital or general practice) rather than through explicit inclusion/exclusion criteria.
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The implications, with respect to predicting the safety of the product in the marketplace, of any of
these populations with limited or no research should be explicitly discussed. In addition, the limitations
of the database with regard to the detection of adverse reactions due to:
• number of patients studied;
• cumulative exposure (e.g. specific organ toxicity);
• long term use (e.g. malignancy)
should be discussed. Where the missing information could constitute an important risk to the target
population, it should be included as a safety concern in RMP module SVIII.
Populations to be considered for discussion should include (but might not be limited to):
• Paediatric population
Children (from birth to 18 years with consideration given to the different age categories as per
ICH-E11, or, if justified, to other developmentally meaningful groups i.e. taking into account
specific organ maturation). If paediatric development has been limited to certain age categories
then the implications for other paediatric age groups should also be discussed.
• Elderly population
Implications for use in patients over the age of 65 should be discussed – with appropriate
consideration given to use in the older end of the age spectrum. The effects of particular
impairments, e.g. renal, hepatic, or of concomitant disease or medication will be discussed mainly
in the appropriate sections below, but discussion in this section should reflect the fact that in the
elderly population many of these factors may co-exist. The cumulative effect of multiple
impairments and multiple medications should be discussed. Consideration of whether particular
laboratory screening should be performed routinely before use of the medicinal product(s) in the
elderly should be discussed. In particular any adverse reactions which might be of special concern
in the elderly e.g. dizziness or central nervous system effects should be explored.
• Pregnant or breast-feeding women
If the target population includes women of child-bearing age, the implications for pregnancy and/or
breast-feeding should be discussed. If the medicinal product is not specifically for use during
pregnancy, any pregnancies which have occurred during the developmental programme and their
outcomes should be discussed. For products where pregnancy should be avoided for safety
reasons, , the discussion on pregnancy should also include an analysis of the reasons why the
contraceptive measures in place during the clinical trials failed and the implications for use in the
less controlled conditions of everyday medical practice.
• Patients with hepatic impairment
• Patients with renal impairment
• Patients with other relevant co-morbidity (e.g. cardiovascular or immunocompromised including
organ transplant patients)
• Patients with disease severity different from that studied in clinical trials
Any experience of use in patients with different disease severities should be discussed, particularly
if the proposed indication is restricted to those patients with a specific disease severity.
• Sub-populations carrying known and relevant genetic polymorphism
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The extent of pharmacogenetic effects and the implications on genetic biomarker use in the target
population should be discussed. Where a proposed drug indication constitutes patients with or
without specific genetic markers, or the clinical development programme has been in patients with
a specific mutation, the marketing authorisation holder should discuss the implications of this for
the target population and explore whether use in patients with an unknown or different genotype
could constitute a safety concern.
If a potentially clinically important genetic polymorphism has been identified but not fully studied in
the clinical development programme, this should be considered as missing information and/or a
potential risk. This should be reflected in the safety specification and pharmacovigilance plan.
Whether it is included as a safety concern for the purposes of risk minimisation will depend upon
the importance of the possible clinical implications.
• Patients of different racial and/or ethnic origins
Genetic variants can influence pharmacodynamics and pharmacokinetics, and subsequently affect
the efficacy and/or safety of the administered drug. Inter-ethnic differences in drug efficacy and
safety have been observed in different ethnic groups due to e.g. genetic polymorphisms.
One example of such inter-ethnic differences is the variation in frequency of the HLA-B*1502
allele. This allele is strongly associated with the occurrence of severe cutaneous adverse reactions
to carbamazepine and has a prevalence of about 10% in some Asian populations, whilst the
prevalence of the allele is negligible in those of European descent. This is why genomic testing is
recommended for patients of some Asian origins when carbamazepine use is planned, while this
testing will not make sense for a patient who is of European descent.
Major inter-ethnic differences in pharmacokinetics of drugs may also occur due to types and/or
frequencies of gene variants coding for drug metabolising enzymes. The consequences of these
inter-ethnic differences could be that the proportion of subjects with particular beneficial effects or
adverse reactions varies, leading to different risk-benefit balances and specific recommendations in
these ethnic populations.
Furthermore, efficacy in patients may be affected by racial origin. One example is that ACE
inhibitors are less potent in black patients of African or Caribbean family origin than in white
patients.
Therefore, information on racial origin may be relevant and valuable for evaluation of efficacy and
safety and for preventing adverse reactions or improving benefits in the target population.
The experience of drug use in patients with different racial and/or ethnic origins should be
discussed including the implications on efficacy and safety, based on pharmacokinetics and
pharmacodynamics, in the target population. If it is likely that efficacy or safety may be affected by
race or ethnicity, consideration should be given to including this either as a safety concern or as a
topic for inclusion in RMP Part IV. Consideration should also be given as to whether post-
authorisation efficacy and/or safety studies are necessary.
V.B.8.5. RMP module SV “Post-authorisation experience”
The purpose of this RMP module is to provide information on the number of patients exposed post
authorisation; how the medicinal product has been used in practice and labelled and off-label use
including use in the special populations mentioned in RMP module SIV. It should also include brief
information on the number of patients included in completed observational studies conducted either to
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elucidate a safety issue or for drug utilisation purposes. Details of significant actions taken to update
information on the safety of the medicinal product should also be provided in this module.
V.B.8.5.1. RMP module SV section “Action taken by regulatory authorities and/or marketing
authorisation holders for safety reasons”
List any significant regulatory action (including those initiated by the marketing authorisation holder),
in any market, taken in relation to a safety concern. Significant regulatory action would include: a
restriction to the approved indication, a new contra-indication, a new or strengthened warning in
section 4.4 of the SPC (or equivalent) or any action to suspend or revoke a marketing authorisation.
This list should be cumulative, and specify the country, action taken and the date as appropriate. Roll-
out in multiple countries of a new safety statement initiated by the MAH can be presented as one
action.
When the RMP is updated, a brief description of the reasons leading to any significant actions since the
last submission of the RMP should be provided. It may be appropriate to add comments if the
regulatory action taken is not applicable to certain products/formulations as authorised in the EU.
V.B.8.5.2. RMP module SV section “Non-study post-authorisation exposure”
Where marketing of the medicinal product has occurred, the applicant/marketing authorisation holder
should provide cumulative data on patients exposed post-marketing. Where possible, the information
should be stratified by relevant variables. These may include age, sex, indication, dose and region (EU
versus non EU). Depending upon the medicinal product, other variables may be relevant such as
number of vaccination courses, route of administration or duration of treatment. If the data are
available, EU use should be broken down into country or sales area.
When deciding which measure to use for exposure data, it is important to consider the way a medicinal
product is used. Exposure data based on the number of kilogrammes of medicinal product sold divided
by the average dose is only valid if the medicinal product is always used at one dose level for a fixed
length of time, which is not the situation with most medicinal products. In paediatric populations or
mixed populations of different indications or age groups, use of this measure alone is inappropriate and
other measures should be used. For example, for medicinal products used chronically, the appropriate
measure may be patient years of use. However, when use is typically limited and utilisation is
determined by pack size (e.g. a course of antibiotics), a simple count of packs sold may be more
appropriate.
If the drug has different routes of administration, e.g. subcutaneous or oral, exposure data should be
presented separately, where possible. Competent authorities may request additional stratification of
exposure data, e.g. exposure in age groups or within different approved indications. However, if the
drug is used in different indications with different dosing schedules or other delineating factors suitable
for stratification, marketing authorisation holders should consider routinely providing such data where
possible.
A more accurate breakdown of drug exposure based on market research should be provided where
possible.
If a drug utilisation study has been performed, for reimbursement or other reasons, the results, as
they reflect use in the real world setting, should be provided.
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V.B.8.5.3. RMP module SV section “Post-authorisation use in populations not studied in
clinical trials”
Where there are data on post-authorisation use in the special populations identified in RMP module SIV
as having no or limited exposure, estimation of the numbers exposed and the method of calculation
should be provided whether or not the usage is on- or off-label. For paediatric use, cross reference
may be made to RMP section “Specific paediatric issues” in RMP module SVI (see V.B.8.6.6.).
Information on the safety profile of the medicinal product in these special populations, as compared
with the rest of the target population, should also be provided. In particular, any information regarding
an increased or decreased benefit in a special population should be provided. Any special populations
found to be at an increased or decreased risk in relation to a particular safety concern should be
discussed under the specific risk in RMP module SVII but reference should be made in this section as to
which risks and populations are affected.
V.B.8.5.4. RMP module SV section “Post-authorisation off-label use”
Post marketing, updates to the safety specification, should include information on EU off-label use; i.e.
the intentional use, for a medical purpose, which is not in accordance with the authorised product
information for a medicinal product. Off-label use includes use in non-authorised paediatric age
categories. Unless specifically requested, it does not include use outside the EU in an indication
authorised in that territory which is not authorised in the EU. EU use in clinical trials conducted as part
of the marketing authorisation holder’s development programme should be included only in RMP
module SIII and not in this section.
Information from drug utilisation studies (or other observational studies where indication is a variable)
should be provided where available. This includes drug utilisation studies which were requested by
national competent authorities for purposes other than risk management. When off label use is a
safety concern or a concern has been raised by the competent authorities regarding off-label use,
marketing authorisation holders should attempt to quantify such use along with a description of the
methods used to arrive at these figures.
V.B.8.5.5. RMP module SV section “Epidemiological study exposure”
Marketing authorisation holders should provide a listing of epidemiological studies which are, or have
been, conducted to elucidate safety or efficacy issues, study drug utilisation or measure effectiveness
of risk minimisation measures. This listing should include studies undertaken by the marketing
authorisation holder itself or funded by them via a grant, whether specific or unconditional. Studies
undertaken by a marketing partner, or where the MAH has been sent the results by a third party,
should also be included. Information on the study title, study type (e.g. cohort, case control),
population studied (including country and other relevant population descriptors), duration of study,
number of persons in each category (e.g. cases, controls, exposure), disease as appropriate, person
time (if appropriate) and study status (completed or on-going) should be provided. If a study has been
published, a reference should be included in this RMP section, a synopsis should be included in RMP
annex 5 and the publication provided in RMP annex 12.
V.B.8.6. RMP module SVI “Additional EU requirements for the safety
specification”
Some safety topics were not included in ICH-E2E but are thought to be of particular interest due to
either EU legislation or prior experience of a safety issue.
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V.B.8.6.1. RMP module SVI section “Potential for harm from overdose”
Special attention should be given to medicinal products where there is an increased risk of harm from
overdose, whether intentional or accidental. Examples include medicinal products where there is a
narrow therapeutic margin or potential for major dose-related toxicity, and/or where there is a high
risk of intentional overdose in the treated population (e.g. in depression). Where harm from overdose
has occurred during clinical trials this should be explicitly mentioned. The potential for harm from
overdose should be discussed in this section and, where appropriate, overdose should be included as a
safety concern in RMP module SVIII and appropriate risk minimisation proposed in RMP part V.
V.B.8.6.2. RMP module SVI section “Potential for transmission of infectious agents”
The applicant/marketing authorisation holder should discuss the potential for the transmission of an
infectious agent. This may be because of the nature of the manufacturing process or the materials
involved. For vaccines, any potential for transmission of live virus should be discussed. For advanced
therapy medicinal products a cross-reference to RMP module SVII (ATMP) may be made.
V.B.8.6.3. RMP module SVI section “Potential for misuse for illegal purposes”
The potential for misuse for illegal purposes should be considered. Misuse, as defined in GVP Module
VI, refers to situations where the medicinal product is intentionally and inappropriately used not in
accordance with the authorised product information. Misuse for illegal purposes has the additional
connotation of an intention of misusing the medicinal product to cause an effect in another person.
This includes, amongst others: the sale, to other people, of medicines for recreational purposes and
use of a medicinal product to facilitate assault. If appropriate, the means of limiting this, e.g. by the
use of colorants and/or flavourings in the dosage form, limited pack size and controlled distribution
should be discussed in the risk minimisation plan.
V.B.8.6.4. RMP module SVI section “Potential for medication errors”
For the purposes of the RMP, medication error refers to any unintended error in the prescribing,
dispensing or administration of a medicinal product while in the control of the healthcare professional,
patient or consumer. Medication errors are an important cause of morbidity and mortality and many
could be prevented or mitigated. They fall broadly into 4 categories:
1. wrong medication;
2. wrong dose (including strength, form, concentration, amount);
3. wrong route of administration;
4. wrong patient
Applicants/marketing authorisation holders should consider routinely the likelihood of medication
errors. In particular, they should assess, prior to marketing, common sources of medication errors.
During the development phase and during the design of a medicinal product for marketing, the
applicant needs to take into account potential reasons for medication error. The naming (taking into
account the Guideline on the Acceptability of Invented Names for Human Medicinal Products Processed
Through the Centralised Procedure 3 ), presentation (e.g. size, shape and colouring of the
pharmaceutical form and packaging), instructions for use (e.g. regarding reconstitution, parenteral
routes of administration, dose calculation) and labelling are among the items to be considered. In
3 See CPMP/328/98 latest version; available on EMA website http://www.ema.europa.eu.
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addition, the Guideline on the Readability of the Label and Package Leaflet of Medicinal Products for
Human Use4 should be followed.
If a product has potential for serious harm when administered by an incorrect route, consideration
should be given as to how such administration can be avoided. This is particularly important when it is
common practice to administer the product at the same time as other medicinal products given by the
hazardous route. In this situation, medication errors should be included as a safety concern.
The need for visual (or physical) differentiation between strengths of the same medicinal product and
between other medicinal products commonly administered or taken at the same time should be
discussed. In addition, if there are other products containing the same active substance on the market
with formulations which are not proven to be bioequivalent, measures to avoid medication error should
be discussed and appropriate risk minimisation activities proposed.
When a medicinal product is likely to be used by a visually impaired population, special consideration
should be given to the potential for medication error. Where appropriate, medication error should be
included as a safety concern and appropriate risk minimisation measures proposed to address the
possibility of medication error due to visual impairment.
Consideration should be given to the prevention of accidental ingestion or other unintended use by
children.
Medication errors identified during product development including clinical trials should be discussed
and information on the errors, their potential cause(s) and possible remedies given. Where applicable
an indication should be given of how these have been taken into account in the final product design.
If during the post-marketing period it becomes apparent that adverse reactions are occurring as a
result of medication errors, this topic should be discussed in the updated RMP and ways of limiting the
errors proposed.
If the formulation or strength of a product is being changed, where appropriate, medication error
should be included as a safety concern and the measures that the marketing authorisation holder will
put in place to reduce confusion between old and new “product” should be discussed in the risk
minimisation plan. Similarly, it may be appropriate to discuss risk minimisation activities in relation to
changes to the presentation, pack size, route of administration or release characteristics of the
medicinal product.
If the product is to be administered with a medical device (integrated or not), consideration should be
given to any safety concerns which could represent a risk to the patient (medical device malfunction).
V.B.8.6.5. RMP module SVI section “Potential for off-label use”
The potential for off-label use should be discussed. Off-label use relates to situations where the
medicinal product is intentionally used for a medical purpose not in accordance with the authorised
product information. This is particularly relevant where a medicinal product has an indication
restricted to a subset of the population within a disease area or there are situations where the
medicinal product must not be given for safety reasons. The potential for use in other disease areas
should also be considered where this is likely.
Where appropriate, use could be made of data on actual use versus authorised use in other markets
and the implications for the authorisation in the EU discussed.
4 See ENTR/F/2/SF/jr (2009)D/89 Eudralex Volume 2C - Regulatory Guidance; available on
http://ec.europa.eu/health/documents/eudralex.
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V.B.8.6.6. RMP module SVI section “Specific paediatric issues”
This section deals with aspects of paediatric use not covered in RMP module SIV.
Issues identified in paediatric investigation plans
Any recommendations for long term follow up of safety or efficacy issues in relation to paediatric use
which are mentioned in the paediatric investigation plan should be detailed here. This section should
clarify if, and how, this had been taken into account in RMP module SVII. If the issue has been
resolved following further development, or is no longer considered of sufficient impact to justify listing
as a safety concern, this should be discussed and justified.
Proposals for specific long term paediatric studies should be considered at the time of application for a
paediatric indication and if felt not to be necessary justification should be provided. If an indication in
adults precedes an application for paediatric use, any registries established to provide data on use of
the product in real medical practice should avoid age related exclusion criteria so that any potential
off-label use in the paediatric population can be included.
In some circumstances, the safety concern identified in the paediatric investigation plan may be
applicable to the whole population being treated. In these cases, consideration should be given as to
whether some of the pharmacovigilance activities and/or risk minimisation activities from the
paediatric investigation plan are appropriate for, and should be extended to cover, the whole
population. For these safety concerns, this RMP section should also include details of how the specific
paediatric aspects will be addressed and all paediatric investigation plan recommendations considered.
Cross-reference may be made to RMP modules SIV and SVII and SVII.
Potential for paediatric off-label use
If the disease or disorder which is being treated or prevented is found in the paediatric population, and
the product is not authorised in all paediatric age groups, the potential for off-label paediatric use in
the non-authorised age groups should be discussed. If there are limited treatment options it should not
be assumed that clinicians will adhere to the labelled indication so it is important that potential
paediatric issues are discussed. Any actual use should be discussed in RMP module SV section “Non-
study post-authorisation exposure” (see V.B.8.5.2.) and in RMP module SV section “Post-authorisation
use in populations not studied in clinical trials” (see V.B.8.5.3.).
V.B.8.7. RMP module SVII “Identified and potential risks”
This RMP module provides information on the important identified and potential risks associated with
use of the product. These should include only the important identified and potential adverse
events/reactions, important identified and potential interactions with other medicinal products, foods
and other substances, and the important pharmacological class effects.
Because of the need for different additional categories of risks to be considered with advanced therapy
medicinal products, a different version of RMP module SVII is available for products classified as
advanced medicinal products. Only one version (either sections V.B.8.7.1 - V.B.8.7.5 or sections
V.B.8.8.1 – V.B.8.8.3) of RMP module SVII should be provided in a RMP.
V.B.8.7.1. RMP module SVII section “Newly identified safety concerns”
Safety concerns (important identified and important potential risks) identified since the last submission
of the RMP should be listed here and further discussed in the appropriate section below. The source of
the safety concern should be stated, whether it is an important identified or important potential risk
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and whether new studies or risk minimisation activities are proposed (with further details in the
appropriate RMP parts).
V.B.8.7.2. RMP module SVII section “Recent study reports with implications for safety
concerns”
Study reports (either interim or final, from whichever type of study), since the last RMP, which contain
results which have a significant impact on an existing safety concern should be discussed here. The
conclusions should be incorporated into the other sections of the safety specification as appropriate
(e.g. RMP module SII; section V.B.8.7.3; V.B.8.7.4; V.B.8.7.5; RMP Module SVI and RMP Module
SVIII).
V.B.8.7.3. RMP module SVII section “Details of important identified and potential risks from
clinical development and post-authorisation experience”
This RMP section should provide more information on the important identified and potential risks. This
RMP section should be concise and should not be a data dump of tables or lists of adverse reactions
from clinical trials, or the proposed or actual contents of section 4.8 of the summary of product
characteristics (SmPC).
What constitutes an important risk will depend upon several factors including the impact on the
individual patient, the seriousness of the risk and the impact on public health (see also V.B.1).
Normally, any risk which is clinically important and which is/is likely to be included in the
contraindications or warnings and precautions section of the summary of product characteristics
(SmPC) should be included here. In addition, risks, which, whilst not normally serious enough to
require specific warnings or precautions but which occur in a significant proportion of the treated
population, affect the quality of the treated person’s life, and which could lead to serious consequences
if untreated should also be considered for inclusion, e.g. severe nausea and vomiting with
chemotherapy.
For some products, disposal of the used product may constitute a safety concern, e.g. transdermal
patches where there may be significant amounts of active substance remaining in the patch when it is
discarded. There may also be occasions where there is an environmental concern over product disposal
because of known harmful effects on the environment, e.g. substances which are particularly
hazardous to aquatic life which should not be disposed of in landfill sites.
Presentation of risk data:
When the information is available, detailed risk data should include the following:
• frequency;
• public health impact (severity and seriousness/reversibility/outcomes);
• impact on the individual patient (effect on quality of life);
• risk factors (including patient factors, dose, at risk period, additive or synergistic factors);
• preventability (i.e. predictability of a risk, whether risk factors have been identified, or possibility of
detection at an early stage which could mitigate seriousness);
• potential mechanism;
• evidence source(s) and strength of the evidence.
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The frequency of important identified risks should be expressed taking into account the source of the
data. For a product already on the market, the reporting rate based on the number of spontaneously
reported adverse events/adverse reactions (in the numerator) and the sales data (in the denominator)
is very likely to underestimate the rate of occurrence of an adverse reaction in an exposed population
and should be avoided. When an accurate frequency is needed for an important identified risk, this
should always be based on systematic studies (e.g. clinical trials or epidemiological studies) in which
both the number of patients exposed to the medicinal product and the number of patients who
experienced the respective identified risk are known.
The denominator should be expressed using the appropriate measure: e.g. number of patients or in
patient-time or equivalent units (courses of treatment, prescriptions, etc.) It should be stated clearly
which frequency parameter is being used: e.g. incidence proportion (patient units in the denominator)
or incidence rate (patient-time units in the denominator). Confidence intervals should be provided.
When using patient-time, the underlying assumption is that the hazard function must be nearly
constant over the follow-up time. Otherwise it should be split into relevant categories where the
assumption of constancy holds. This may be particularly important if treatment duration is a risk
factor. Where appropriate, the period of major risk should be identified. Identified risk incidence rates
should be presented for the whole population and for relevant population categories.
For important identified risks, the excess (relative incidence compared to a specified comparator
group) should be given. Time to event data should be summarised using survival techniques.
Cumulative hazard functions may also be used to represent the cumulative probability of occurrence of
an adverse reaction in the presence of competing events.
For potential risks, the background incidence/prevalence in the target population(s) should be
provided.
For most RMPs involving single products, risks which relate specifically to an indication or formulation
can usually be handled as individual safety concerns, e.g. accidental intravenous administration could
be a safety concern in a single product with both oral and subcutaneous forms.
For RMPs covering multiple products where there may be significant differences in the identified and
potential risks for different products, it may be appropriate to categorise the risks to make it clearer
which risks relate to which product. Headings which could be considered include:
• Risks relating to the active substance
This would include important identified or potential risks which are common to all formulations,
routes of administration and target populations. It is likely that most risks will fall into this
category for the majority of products.
• Risks related to a specific formulation or route of administration
Examples might include an RMP with two products: one a depot intramuscular formulation and the
other an oral formulation. Additional concerns relating to accidental intravenous administration
clearly would not be applicable to the oral product.
• Risks relating to a specific target population
The paediatric population is an obvious example of a target population where there may be
additional risks relating to physical, mental and sexual development which would not be relevant to
a product intended solely for adult patients.
• Risks associated with switch to non-prescription status.
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Division of identified and potential risks using headings should only be considered when the risks
clearly do not apply to some products and lack of separation could cause confusion.
V.B.8.7.4. RMP module SVII section “Identified and potential interactions including food-
drug and drug-drug interactions”
Identified and potential pharmacokinetic and pharmacodynamic interactions should be discussed in
relation to both the treatments for the condition, but also in relation to commonly used medications in
the target population. For each, the evidence supporting the interaction and possible mechanism
should be summarised, and the potential health risks posed for the different indications and in the
different populations should be discussed. Interactions which are important clinically should be
included as a safety concern in RMP module SVIII “Summary of the safety concerns.”
V.B.8.7.5. RMP module SVII section “Pharmacological class effects”
Important risks which have not been included in RMP module SVII “Details of important identified and
potential risks from clinical development and post-authorisation experience” (above) but which are
believed to be common to the pharmacological class should be discussed here. The discussion should
include the mechanism, the impact (severity and duration), frequency seen with other members of the
same or similar pharmacological class.
For risks which have been included in the RMP section SVII “Details of important and identified and
potential risks from clinical development and post-authorisation experience” above, all that is required
in this RMP section are the frequencies seen with the medicinal product compared with those seen with
other products in the same or similar pharmacological class.
If there is evidence that a risk, which is common to other members of the pharmacological class, is not
thought to be a safety concern with the concerned medicinal product, details, and the evidence
supporting this, should be provided and discussed.
V.B.8.8. RMP module SVII “Identified and potential risks (ATMP version)”
Advanced therapy medicinal products (ATMPs) because of their nature may have specific risks that are
usually not applicable to other non-advanced therapy medicinal products (see Guideline on Safety and
Efficacy Follow-up – Risk Management of Advanced Therapy Medicinal Products5). For this reason, for
ATMPs, this ATMP specific version of RMP module replaces the standard RMP module SVII.
Although not all of the risks listed in section V.B.8.8.3. are unique to ATMPs or applicable to all ATMPs,
they represent the most relevant ones which need to be considered.
V.B.8.8.1. RMP module SVII section “Newly identified safety concerns (ATMP)”
Safety concerns (important identified and important potential risks) identified since the last submission
of the RMP should be listed here and further discussed in the appropriate section below. The source of
the safety concern should be stated, whether it is an important identified or important potential risk
and whether new studies or risk minimisation activities are proposed (with further details in the
appropriate RMP parts).
5 EMEA/149995/2008; available on EMA website http://www.ema.europa.eu
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V.B.8.8.2. RMP module SVII section “Recent study reports with implications for safety
concerns (ATMP)”
Study reports (either interim or final), since the last RMP, which contain results which have a
significant impact on an existing safety concern should be discussed here. The conclusions should be
incorporated into the other sections of the safety specification as appropriate (e.g. RMP module SII;
section V.B.8.8.3; RMP Module SVI and RMP Module SVII).I
V.B.8.8.3. RMP module SVII section “Details of important identified and potential risks
(ATMP)”
This section should provide more information on the most important identified and potential risks. This
section should be selective and should not be a data dump of tables or lists of adverse reactions from
clinical trials, or the proposed or actual contents of section 4.8 of the summary of product
characteristics (SmPC).
What constitutes an important risk will depend upon several factors including the impact on the
individual, the seriousness of the risk and the impact on public health. Normally, any risk which is
clinically important and is/is likely to be included in the warnings and precautions section of the
summary of product characteristics should be included here. In addition, risks, which, whilst not
normally serious enough to require specific warnings or precautions but which occur in a significant
proportion of either the patient or donor, affect the quality of life, and which could lead to serious
consequences if untreated should also be considered for inclusion. The additional risks specific to
ATMPs which should be considered for discussion include:
• risks to living donors, for instance:
− risks to living donors related to their conditioning prior to procurement (e.g.
immunosuppression, cytotoxic agents, growth factors);
− risks to living donors related to surgical/medical procedures used during or following
procurement, irrespective of whether the tissue was collected or not;
• risks to patients related to quality characteristics of the product, in particular:
− species of origin and characteristics of cells (and related body fluids, biomaterials,
biomolecules) that are used during manufacturing, and the safety testing performed;
− characteristics of vectors for gene therapy medicinal products;
− biologically active substances used in manufacturing (e.g. enzymes, antibodies, cytokines,
sera, growth factors, antibiotics);
− quality assurance and characteristics of the finished product in terms of defined composition,
stability, biological activity, and purity with reference to non-physiologic proteins and
fragments thereof;
− risk related to transmissible diseases (e.g. viral, bacterial, parasitical infections and
infestations, but also malignant disease);
• risks to patients related to the storage and distribution of the product, for instance:
− risks related to preservation, freezing and thawing;
− risks of breaking the cold chain or other type of controlled temperature conditions;
− risks related to stability of the product;
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• risks to patients related to administration procedures, for instance:
− biologically active substances used in preparation of the product prior to administration (e.g.
enzymes, antibodies, cytokines, sera, growth factors, antibiotics);
− risks related to conditioning of the patient;
− risks of related medical or surgical procedures (e.g. anaesthesia, infusion, transfusion,
implantation, transplantation or other application method);
− risks related to clinical follow-up (e.g. immunosuppression as co-medication or as necessary
for treatment of complications, diagnostic procedures, hospitalisation);
− risks related to mistakes or violations of the standard procedures for administration of the
product (e.g. different administration procedures used by different healthcare
establishments/healthcare professionals resulting in differing results);
• risks related to interaction of the product and the patient, for instance:
− unwanted immunogenicity and its consequences (including e.g. anaphylaxis, graft versus host
disease, graft rejection, hypersensitivity reactions, immune deficiencies);
− risks related to both intended and unintended genetic modification of the patient’s cells
(apoptosis, change of function, alteration of growth and/or differentiation, malignancy);
− early and late consequences of homing, grafting, differentiation, migration and proliferation;
− risks related to infection with vectors used in gene therapy medicinal products (type of vector,
target cells, persistence, potential for latency and reactivation, potential for integration of
genetic material into the host genome, prolonged expression of the transgene, altered
expression of the host’s genes);
• risks related to scaffolds, matrices and biomaterials (e.g. biodegradation, mechanical factors);
• risks related to persistence of the product in the patient, e.g.:
− availability of rescue procedures or antidotes and their risks;
− late complications, particularly malignancies and auto-immunity;
− considerations on the potential impact of previous, concomitant, or future therapies typical for
the diagnosis or treatment of the respective disease on the product, or vice versa impact of the
product on those other therapies (e.g. an immunoglobulin treatment later in life could impact
on expression of the introduced gene by antibody interaction);
• risks related to re-administration, for instance:
− immune reactions - anaphylaxis, neutralising antibodies;
− risks related to repeated surgical or administration procedures;
• risks to close contacts, for instance:
− based on the environmental risk assessment, virus shedding and its consequences;
• specific parent-child risks, for instance:
− risk of germ line integration of transgene, or other genetic transformation of the germ line;
− foetal transmission (of e.g. vectors, biologically active substances, cells, infectious agents);
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− trans-mammary exposure of children in breast-feeding women (to e.g. vectors, biologically
active substances, cells, infectious agents).
V.B.8.9. RMP module SVIII “Summary of the safety concerns”
At the end of the RMP part “Safety specification” a summary should be provided of the safety concerns.
A safety concern is:
• an important identified risk;
• an important potential risk; or
• missing information (see Annex I).
It is noted that the ICH definition of safety concern is: an important identified risk, important potential
risk or important missing information, i.e. includes the qualifier “important” in relation to missing
information (see Annex IV, ICH-E2C(R2) Guideline). The ICH-E2E Guideline (see Annex IV) uses the
terms safety issue and safety concern interchangeably with the same definition for safety concern as
defined in the ICH-E2C(R2) Guideline.
The change of the EU term, to name this concept “missing information” rather than “important missing
information”, is to be clear that in the EU a marketing authorisation cannot be granted if there are
unacceptable gaps in knowledge, in accordance with Article 12 of REG (EC) No 726/2004 a marketing
authorisation shall be refused if the quality, safety or efficacy are not properly or sufficiently
demonstrated.
For RMPs covering multiple products where there may be significant differences in the important
identified and important potential risks for different products, similar to the presentation of risks in
RMP module SVII, it may be appropriate to subdivide the summary of safety concerns under specific
headings with the relevant identified and potential risks under each heading. Headings which could be
considered include:
• safety concerns relating to the active substance;
• safety concerns related to a specific formulation or route of administration;
• safety concerns relating to the target population;
• risks associated with switch to non-prescription status.
Division of safety concerns by headings should only be considered when the risks clearly do not apply
to some products and inclusion as a single list could cause confusion.
V.B.9. RMP Part III “Pharmacovigilance plan”
The purpose of the pharmacovigilance plan is to discuss how the applicant/marketing authorisation
holder plans to identify and/or characterise the risks identified in the safety specification. It provides a
structured plan for:
• the identification of new safety concerns;
• further characterisation of known safety concerns including elucidation of risk factors;
• the investigation of whether a potential safety concern is real or not;
• how missing information will be sought.
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It does NOT include actions intended to reduce, prevent or mitigate risks
The pharmacovigilance plan should be based on the safety concerns summarised in RMP module SVIII
of the safety specification. Early discussions between competent authorities and the marketing
authorisation holder or applicant are recommended to identify whether, and which, additional
pharmacovigilance activities are needed. It is important to note that only a proportion of risks are
likely to be foreseeable and therefore signal detection, which is part of routine pharmacovigilance, will
be an important element in identifying new risks for all products.
Pharmacovigilance activities can be divided into routine pharmacovigilance activities and additional
pharmacovigilance activities. For each safety concern, the applicant/marketing authorisation holder
should list their planned pharmacovigilance activities for that concern. Pharmacovigilance plans should
be proportionate to the risks of the product. If routine pharmacovigilance is considered sufficient for
post-authorisation safety monitoring, without the need for additional actions (e.g. safety studies)
“routine pharmacovigilance” should be entered against the safety concern.
V.B.9.1. RMP part III section “Routine pharmacovigilance activities”
Routine pharmacovigilance is the set of activities required to fulfil the legal requirements for
pharmacovigilance contained within Directive 2001/83/EC and Regulation (EC) No 726/2004. The
Pharmacovigilance System Master File (see Module II) contains details of the system and processes
each marketing authorisation applicant/holder has in place to achieve this. These details are not
required to be submitted in the RMP.
In certain situations, the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee for
Medicinal Products for Human Use (CHMP) or the Coordination Group for Mutual recognition and
Decentralised Procedures – Human (CMDh) may make recommendations for specific activities related
to the collection, collation, assessment and reporting of spontaneous reports of adverse reactions
which differ from the normal requirements for routine pharmacovigilance (see Module I). If these
recommendations include recording of tests (including in a structured format) which would form part of
normal clinical practice for a patient experiencing the adverse reaction then this requirement would still
be considered as routine. The routine pharmacovigilance section of the pharmacovigilance plan should
be used in these circumstances to explain how the applicant will modify its routine pharmacovigilance
activities to fulfil any special PRAC, CHMP or CMDh recommendations on routine pharmacovigilance.
However, if the recommendation includes the submission of tissue or blood samples to a specific
laboratory (e.g. for antibody testing) which is outside “normal” clinical practice, then this would
constitute an additional PhV activity.
Specific adverse reaction follow-up questionnaires
Where an applicant/marketing authorisation holder is requested, or plans to use, specific
questionnaires to obtain structured information on reported adverse reactions of special interest,
copies of these forms should be provided in RMP annex 7 and will be made available upon request.
Applicants/marketing authorisation holders are encouraged to use the same or similar questionnaires
for the same adverse event to decrease the burden on healthcare professionals.
Use of specific questionnaires as a follow-up to a reported suspected adverse reaction is considered to
be routine pharmacovigilance.
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V.B.9.2. RMP part III section “Additional pharmacovigilance activities”
Additional Pharmacovigilance activities may be non-clinical studies, clinical trials or non- interventional
studies. A safety concern may have no, or a number of, additional pharmacovigilance activities
associated with it depending upon its nature, the degree to which it has already been characterised,
and the feasibility of studying it. Applicants/marketing authorisation holders should consider the
situations when additional pharmacovigilance activities are needed. For example, a medicinal product
intended for chronic use may only have relatively short term follow up data at the time of
authorisation. Long term follow-up of patients from the clinical trial population or a cohort study may
provide additional reassurance on the long term effects of the medicinal product. A medicinal product,
where there is conflicting pre-clinical data, e.g. carcinogenicity in only one species, may also require
long term follow-up of a cohort of patients to confirm that there is not an increased risk of cancer in
human use. Another example, when additional pharmacovigilance activities should be considered, is
when a potential risk with an individual medicinal product has a significant background incidence in the
target population(s), leading to difficulties in distinguishing between the effects of the medicinal
product and the “normal” incidence. When any doubt exists about the need for additional
pharmacovigilance activities, consultation with a competent authority should be considered.
The objective(s) of additional pharmacovigilance activities will normally differ according to the safety
concern to be addressed. For important identified and potential risks, objectives may be to measure
the incidence rate in a larger or a different population, to measure the rate ratio or rate difference in
comparison to a reference medicinal product, to examine how the risk varies with different doses and
durations of exposure, to identify risk factors or to assess a causal association. For missing
information, the objective may simply be to investigate the possibility of a risk or to provide
reassurance about the absence of a risk.
The threshold for investigating a safety concern further will depend upon the indication, the target
population, and the likely impact on public health. For example, a safety concern with a vaccine might
have a lower threshold for investigation than the same issue in a medicinal product used in the
palliative treatment of metastatic cancer.
Studies in the pharmacovigilance plan should relate to the safety concerns identified in the safety
specification whether the studies are to identify and characterise risks, or to assess the effectiveness of
risk minimisation activities. The applicant/marketing authorisation holder should include all studies
designed to address the safety concern or measure the effectiveness of risk minimisation measures.
This includes all post-authorisation safety studies which are initiated, managed or financed by
marketing authorisation holders, voluntarily, or pursuant to obligations imposed by a competent
authority [REG Art 10, Art 10a(1)], DIR Art 21a, Art 22a(1), Art 22c]. Studies requested by other
regulatory authorities (including those outside of the EEA) to investigate a specific safety concern
should also be included. If a marketing authorisation applicant/holder has a marketing partner, studies
designed to address a particular safety concern which are initiated, managed or financed by that
partner should be included in the pharmacovigilance plan, if possible.
If, when reviewing a study protocol, a study is thought not to have as its primary focus one of the
objectives of a PASS (as described in Module VIII), or a PAES, or the study is judged to be unlikely to
achieve its stated scientific purpose, the applicant/marketing authorisation holder will be required to
modify it or remove it from the pharmacovigilance plan and resubmit the RMP.
Pharmacoepidemiology studies included in the pharmacovigilance plan should be designed and
conducted according to the respective legislation in place and recommendations in the Guidelines for
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Good Pharmacoepidemiology Practices (GPP)6 and the ENCePP Guide on Methodological Standards in
Pharmacoepidemiology7. For studies involving children, the Guideline on Conduct of Pharmacovigilance
for Medicines Used by the Paediatric Population8 should be consulted. It is highly recommended that
expert advice is sought on the design and conduct of any studies – whether by the scientific advice
procedure or by consulting known experts in the appropriate field. The responsibility for the scientific
value of study protocols remains with applicants or marketing authorisation holders, even if they have
been previously discussed with competent authorities.
Further guidance on the conduct of post-authorisation safety studies (PASS) is given in Module VIII.
For some safety concerns, additional pharmacovigilance activities other than pharmacoepidemiology
studies may be required, e.g. pharmacokinetic studies, clinical trials or further pre-clinical work. The
appropriate guidelines and legislation should be followed in the conduct of these studies.
Protocols for studies in the pharmacovigilance plan should be provided in RMP annex 6 until completion
of the study and submission to the competent authorities of the final study report. Changes to the
protocol which do not affect milestones or due dates are not considered to be updates to the RMP (see
also Module VIII).
For studies conducted as an obligation, the marketing authorisation holder shall submit the study
protocol, in English except for studies to be conducted in only one Member State that requests the
study [DIR Art 22a]. For other studies, if the study protocol or the study report is written in another
language, the marketing authorisation should facilitate access to study information by including an
English translation of the title, the abstract of the study protocol and the abstract of the final study
report (see Module VIII).
Synopses of study reports from additional pharmacovigilance activities should be included in RMP
annex 9. The impact of the new data on the risk-benefit balance of the medicinal product should be
carefully assessed and the safety specification, pharmacovigilance plan and risk minimisation measures
updated accordingly.
V.B.9.2.1. Particular situations with post authorisation safety studies
This section should be read in conjunction with Module VIII on post-authorisation safety studies.
a. Studies to measure the effectiveness of risk minimisation measures
Post-authorisation safety studies (PASS) include in their definition studies which measure the
effectiveness of risk management measures. Studies looking at the effectiveness of risk minimisation
measures should be included in the pharmacovigilance plan against the specific safety concern(s) as
well as described in detail in the risk minimisation plan. Further guidance on measuring the
effectiveness of risk minimisation measures can be found in Module XVI.
b. Drug utilisation studies
Drug utilisation studies are sometimes requested by national competent authorities to monitor drug
usage in their country, often in relation to reimbursement discussions. However, although they may
not be initiated to collect safety data, they can provide useful information on whether risk minimisation
6 International Society for Pharmacoepidemiology. Guidelines for good pharmacoepidemiology practices (GPP).
Pharmacoepidemiol Drug Saf. 2005; 14 (8): 589-595; available on the ISPE website
http://www.pharmacoepi.org/resources/guidelines_08027.cfm.
7 ENCePP Guide on Methodological Standards in Pharmacoepidemiology” EMA/95098/2010; available on
http://www.encepp.eu.
8 EMEA/CHMP/PhVWP/235910/2005; available on
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000087.jsp&mid=WC
0b01ac0580025b90&jsenabled=true.
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activities are effective and on the demographics of target populations. Ideally, requests for drug
utilisation studies by national competent authorities in one or more EU countries should be identified to
the Rapporteur/Reference Member State pre-opinion and included in the pharmacovigilance plan.
However, these studies are sometimes requested post-authorisation by authorities not involved in
medicinal product licensing. In these circumstances, the studies should be included in the next update
to the RMP.
c. Joint studies
If safety concerns apply to more than one medicinal product, the national competent authority or the
Agency shall, following consultation with the PRAC, encourage the marketing authorisation holders
concerned to conduct a joint PASS [DIR Art 22a(1), REG Art 10a(1)]. The conduct of a joint study may
also be appropriate where there are limited patients (rare diseases) or the adverse reaction is rare.
The national competent authority or the Agency should facilitate the agreement of the concerned
marketing authorisation holders in developing a single protocol for the study and conducting the study.
Where the PRAC agrees to impose the same PASS on more than one marketing authorisation holder
and the concerned marketing authorisation holders have failed to agree a common protocol within a
reasonable period of time, as determined by the PRAC, the national competent authority or the
Agency, with input from the PRAC, may define either a common core protocol or key elements within a
protocol which the concerned marketing authorisation holders will have to implement within a
timescale laid down within the request. Hence, the study would become a condition of the marketing
authorisation and be reflected in the RMP. In some circumstances, the encouragement to do joint
studies may relate to a single active substance where there are multiple marketing authorisation
holders for the same active substance.
d. Registries
A registry is an organised system that uses observational methods to collect uniform data on specified
outcomes in a population defined by a particular disease, condition, or exposure. A registry can be
used as a data source within which studies can be performed. Entry in a registry is generally defined
either by diagnosis of a disease (disease registry) or prescription of a drug (exposure registry).
Registries should ideally include a comparator group so a disease registry will usually be more suitable
than a registry confined to a specific product. However, if, an applicant/marketing authorisation holder
institutes a registry as part of an agreed RMP, the protocol for the registry will allow all patients who
are prescribed the active substance or who have the same disease, as appropriate, to be entered in the
registry. Entry to the registry should not be conditional on being prescribed a product with a particular
invented name or marketing authorisation holder unless there are clear scientific reasons for this. The
same applies to similar biological products.
Unless there are over-riding public health or scientific concerns which lead to mandatory inclusion in a
registry, refusal to enter a registry should not normally be a reason for refusing access to a medicine.
V.B.9.3. RMP part III section “Action plans for safety concerns with
additional pharmacovigilance requirements”
For safety concerns with additional pharmacovigilance activities only, the action plan for each safety
concern should be presented according to the following structure:
• safety concern;
• proposed action(s);
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• individual objectives of proposed action(s) (i.e. what aspects of the safety concern they are
intended to characterise); and
for each action:
• details of individual action;
− steps; and
− milestones (including expected dates).
As well as listing any additional phamacovigilance activities under “proposed actions,” protocols (draft
or otherwise) for any formal studies should be provided in RMP annex 6. Marketing authorisation
applicants/holders should also follow the requirements detailed in Module VIII, where appropriate. It is
recommended that the ENCePP Guide on Methodological Standards in Pharmacoepidemiology 9
including the ENCePP Checklist for Study Protocols 10 , should be referred to when considering
epidemiological protocol design.
V.B.9.4. RMP part III section “Summary table of additional
pharmacovigilance activities”
The pharmacovigilance plan describes pharmacovigilance activities designed to identify and
characterise risks associated with the use of a medicinal product. Some may be imposed as conditions
of the marketing authorisation (MA) either because they are key to the benefit-risk of the product, or
because they are specific obligations in the context of a MA under exceptional circumstances. If the
obligation is a non-interventional PASS, it will be subject to the supervision as described in Art 107
(m)-(q) and the format and content as specified in the EC implementing measures.
The pharmacovigilance plan also includes studies that are conducted or financed by the marketing
authorisation holder to address particular safety concerns and so includes studies which are not
obligations in the above sense. These studies may be on-going or planned, may have been requested
by another regulatory authority, may have been specifically requested by the CHMP or may have been
suggested by the marketing authorisation applicant/holder and agreed with the CHMP as forming part
of the pharmacovigilance plan. They may also be conducted to evaluate the effectiveness of risk
minimisation activities.
Finally, the Pharmacovigilance Plan also has a role in providing an overview of studies which, although
not part of the formal agreed plan to identify and characterise specific safety concerns, the Rapporteur,
Reference Member State or national competent authority needs to be aware of. These studies are
typically requested post-authorisation by a national competent authority for reimbursement reasons
e.g. drug utilisation studies.
The summary table of the pharmacovigilance plan should provide clarity to all stakeholders as to which
category an activity in the pharmacovigilance plan falls under, i.e.:
1. Imposed obligations in the meaning of Art. 10/10a and 21a/22a included as a condition of the MA;
2. Specific Obligations in the framework of a MA under exceptional circumstances. These studies will
also be reflected in Annex II to the marketing authorisation (or national equivalent);
3. Required to investigate a safety concern in the RMP or to evaluate the effectiveness of risk
minimisation activities;
9 ENCePP Guide on Methodological Standards in Pharmacoepidemiology” EMA/95098/2010; available on
http://www.encepp.eu.
10 ENCePP Checklist for Study Protocols”, EMEA/540136/2009; available on http://www.encepp.eu.
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4. Other studies conducted by MAH which may provide safety information but are not considered to be
of significant importance in investigating a safety concern or the effectiveness of risk minimisation
activities.
Table V.2: Attributes of different PhV activities
Type of activity
In
Annex
II of
Opinion
(CAPs
only)
Category
in
Summary
table of
PhV
activities
Status
Supervised
under
Article
107m
Supervised
under
Article 107
n-q
Imposed
PASS
“Interventional”*
X 1
Mandatory
and subject
to penalties
Non-
interventional X 1
Mandatory
and subject
to penalties
X X
Specific
obligation
“Interventional”*
X 2
Mandatory
and subject
to penalties
Non-
interventional X 2
Mandatory
and subject
to penalties
X X
Required “interventional”*
3
Legally
enforceable
Non-
interventional
3
Legally
enforceable
X
Stated
“interventional”*
4
Not
enforced
Non-
interventional
4
Not
enforced
X
*Clinical interventional studies are subject to the requirements of Directive 2001/20/EC. Non clinical
interventional studies are subject to the legal and ethical requirements related to the protection of
laboratory animals, and Good Laboratory Practice as appropriate.
For activities in categories 1-3, the following summary table should be used:
Description of Activity Milestones
(may be several
per activity)
Due Date
(may be several
per activity)
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For activities in category 4 the following summary table should be used:
Description of Activity Expected date
when results
will be
available
V.B.10. RMP part IV “Plans for post-authorisation efficacy studies”
Efficacy, as assessed at the time of authorisation, is based on data from clinical trials which, by their
nature, are of relatively limited duration (e.g. usually between 6 months to 3 years). The benefit
(efficacy of the medicine) risk balance must be positive for a medicine to be authorised. Whereas it is
recognised that many risks will be identified post authorisation, there is an implicit assumption that
efficacy remains relatively constant over time. This may not always be valid.
For most medicines there will not be a need for post-authorisation efficacy studies. However, there
may be circumstances where efficacy may vary over time and also patients in whom this assumption of
constant efficacy may not be true and where longer term efficacy data post authorisation is necessary.
The regulations on paediatric medicinal products (Regulation (EC) No 1901/2006)11, and advanced
therapy medicinal products (Regulation (EC) No 1394/2007)12 provide the legal basis and specify the
potential need for long term follow-up of efficacy as part of post-authorisation surveillance for certain
medicinal products namely:
• applications for a marketing authorisation that include a paediatric indication;
• applications to add a paediatric indication to an existing marketing authorisation;
• application for a paediatric use marketing authorisation;
• advanced therapy medicinal products.
In addition, Article 10a(1) of Regulation (EC) No 726/2004 and Article 21a(f) and Article 22a(1) of
Directive 2001/83/EC, provide the legal basis for requiring post-authorisation efficacy studies for
products where there are concerns about efficacy which can only be resolved after the product has
been marketed, or when knowledge about the disease or the clinical methodology used to investigate
efficacy indicate that previous efficacy evaluations may need significant revision.
The requirement for efficacy studies post authorisation refers solely to the current indication(s) and not
to studies investigating additional indications.
V.B.10.1. RMP part IV section “Summary of existing efficacy data”
As background to any proposed post-authorisation efficacy studies, and to provide context for the
summary of the RMP, there should be a summary of the efficacy of the product and the studies and
endpoints on which it was based. Where the RMP covers more than one medicinal product, the
11 Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal
products for paediatric use
12 Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy
medicinal products
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information should be provided by medicinal product to permit easy extraction for the summary of the
RMP module. Similarly medicinal products with more than one indication should have a separate
summary of efficacy for each indication.
The summary of efficacy (one page maximum per indication/population) should be in lay language and
the following should be considered for inclusion:
• current (gold) standards of treatment;
• where the medicinal product fits in the therapeutic armamentarium (i.e. 1st line, relapse, etc.);
• a brief statement of the standard against which the medicine was judged;
• number of patients in pivotal studies and treatment regimes;
• results in lay language.
The following areas should be discussed briefly and the need for further studies post authorisation
evaluated:
• the robustness of the endpoints on which the efficacy evaluation is based;
• applicability of the efficacy data to all patients in the target population;
• factors which might affect the efficacy of the product in everyday medical practice;
• variability in benefits of treatment for sub populations.
For updates to the RMP, any subsequent data which impacts on efficacy should be mentioned and its
impact on the benefits of the medicinal product discussed.
V.B.10.2 Tables of post-authorisation efficacy studies
A summary table showing an overview of the planned studies together with timelines and milestones
should be provided here with the (draft) protocols for these studies included in RMP annex 8.
Efficacy studies which are specific obligations and/or conditions of the marketing authorisation should
also be included in this part of the RMP.
It should be noted that the Commission may adopt a delegated act on the situations where efficacy
studies may be required and the Agency shall adopt scientific guidance on post-authorisation efficacy
studies.
Efficacy studies which are specific obligations and/or conditions of the MA:
Description of Study Milestones
(may be several
Per activity)
Due Date
(may be several
Per activity)
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Other efficacy/effectiveness studies:
Description of Study Milestones
(may be several
Per activity)
Due Date
(may be several
Per activity)
V.B.11. RMP Part V “Risk minimisation measures”
On the basis of the safety specification, a marketing authorisation applicant/holder should assess what
risk minimisation activities are needed for each safety concern. The risk minimisation plan should
provide details of the risk minimisation measures which will be taken to reduce the risks associated
with individual safety concerns. It is not possible to provide precise guidance on which risk
minimisation activity should be used in a given situation as each safety concern needs to be considered
on a case-by-case basis and will depend upon the severity of the risk, the healthcare setting, the
indication, the pharmaceutical form and the target population. A safety concern may be addressed
using more than one risk minimisation measure.
For active substances where there are individual products with substantially different indications or
target populations, it may be appropriate to have a risk minimisation plan specific to each product.
Examples when multiple risk minimisation plans could be considered include:
• an active substance where there are products with both prescription only and non-prescription
legal status;
• medicinal products where there are major risks, and the indications cross areas of medical
expertise. In the latter case, there could be diverse educational needs for different specialists since
the areas of specialised knowledge will be distinct. For example an active substance which causes
important QT prolongation would most likely not need educational material explaining the
implications of this and the interactions with other products if the product were intended solely for
use by cardiologists in a hospital setting but might need educational material if intended for use in
general practice or orthopaedic surgery where it is unlikely that prescribers will have this specialist
knowledge;
• active substances where there are major risks which differ according to the target population.
Risk minimisation activities may consist of routine risk minimisation (e.g. measures associated with
locally authorised product labelling) or additional risk minimisation activities (e.g. Direct Healthcare
Professional Communications/educational materials/controlled distribution systems). All risk
minimisation measures should have a clearly identifiable objective.
All risk minimisation measures should be reviewed at regular intervals and their effectiveness assessed
(see V.B.11.4.).
Additional risk minimisation measures and the assessment of the effectiveness of risk minimisation
measures in general is discussed in more detail in Module XVI.
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V.B.11.1. RMP part V section “Routine risk minimisation”
Routine risk minimisation activities are those which apply to every medicinal product. These relate to:
• the summary of product characteristics;
• the labelling;
• the package leaflet;
• the pack size(s);
• the legal status of the product.
The summary of product characteristics (SmPC) and the package leaflet are important tools for risk
minimisation as they constitute a controlled and standardised format for informing healthcare
practitioners and patients about the medicinal product. The Guideline on Summary of Product
Characteristics 13 provides guidance on how information should be presented. As discussed in
V.B.8.6.4., the design of the packaging, and even the formulation itself, may play an important role in
preventing medication error.
a. Pack size
Since every pack size is specifically authorised for a medicinal product, planning the number of
“dosage units” within each pack, and the range of pack sizes available can be considered a form of
routine risk management activity. In theory, controlling the number of “dosage units” should mean
that patients will need to see a healthcare professional at defined intervals: increasing the opportunity
for testing and reducing the length of time a patient is without review. In extreme cases, making units
available in only one pack size to try to link prescribing to the need for review may be considered.
A small pack size can also be useful, especially if overdose is thought to be a major risk or if the
potential for drugs to get into the general population needs to be controlled.
b. Legal status
All medicinal products in the EU have a legal status. Controlling the conditions under which a
medicinal product may be made available can reduce the risks associated with its use or misuse. This
can be achieved by controlling the conditions under which a medicinal product may be prescribed, or
the conditions under which a patient may receive a medicinal product.
When a marketing authorisation is granted, it must include details of any conditions or restrictions
imposed on the supply or the use of the medicinal product, including the conditions under which a
medicinal product may be made available to patients. The conditions under which a medicinal product
is made available is commonly referred to as the “legal status” of a medicinal product. Typically it
includes information on whether or not the medicinal product is subject to medicinal prescription. It
may also restrict where the medicinal product can be administered (e.g. in a hospital, but see below)
or by whom it may be prescribed (e.g. specialist).
For medicinal products only available on prescription, additional conditions may be imposed by
classifying medicinal products into those available only upon either a restricted medical prescription or
a special medical prescription.
13 http://ec.europa.eu/health/files/eudralex/vol-2/c/smpc_guideline_rev2_en.pdf
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Restricted medical prescription
This may be used to control who may initiate treatment, prescribe the medicinal product and the
setting in which the medicine can be given or used. According to EU legislation, when considering
classification of a medicinal product as subject to restricted medical prescription, the following factors
shall be taken into account:
• the medicinal product, because of its pharmaceutical characteristics or novelty or in the interests of
public health, is reserved for treatments which can only be followed in a hospital environment;
• the medicinal product is used for the treatment of conditions which must be diagnosed in a hospital
environment or in institutions with adequate diagnostic facilities, although administration and
follow up may be carried out elsewhere; or
• the medicinal product is intended for outpatients but its use may produce very serious adverse
reactions requiring prescription drawn up as required by a specialist and special supervision
throughout the treatment [DIR Art 71(3)].
In the case of an application for a marketing authorisation submitted in accordance with the centralised
procedure, the CHMP is responsible for recommending the legal status to the Commission. Although
the use of legal status is not an activity that can be used directly by a marketing authorisation
applicant for the purposes of risk reduction, the marketing authorisation applicant could request the
competent authority to consider a particular legal status and this is indicated in the SmPC.
However, the definition of what constitutes a specialist is not uniform throughout the Member States
so, in practice, the term “specialist” is usually phrased in section 4.2 of the summary of product
characteristics (SmPC) as: “treatment by a physician experienced in the treatment of <the disease>”.
Although restricting to use in a hospital environment may in practice ensure that the medicinal product
is always prescribed by a specialist, this needs to be balanced against the inconvenience to patients if
they need to attend a hospital for every prescription. Care also needs to be taken when considering
where a medicinal product can be safely administered. For example the term “clinic” has different
connotations depending upon the country. For this reason, the type of equipment needed should be
specified rather than a location: e.g. “use in a setting where resuscitation equipment is available.”
Special medical prescription
For classification as subject to special medical prescription, the following factors shall be taken into
account:
• the medicinal product contains, in a non-exempt quantity, a substance classified as a narcotic or a
psychotropic substance within the meaning of the international conventions in force, such as the
United Nations Conventions of 1961 and 1971; or
• the medicinal product is likely, if incorrectly used, to present a substantial risk of medicinal abuse,
to lead to addiction or be misused for illegal purposes; or
• the medicinal product contains a substance which, by reason of its novelty or properties, could be
considered as belonging to the group envisaged in the previous indent as a precautionary measure
[DIR Art 71(2)].
Categorisation at Member State level
There is the possibility of implementing further sub-categories at Member State level which permits the
Member States to tailor the broad classifications described above to their national situation. The
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definitions and therefore also the implementation varies in those Member States where the sub-
categories exist.
The majority of safety concerns may be adequately addressed by routine risk minimisation activities.
However, for some risks, routine risk minimisation activities will not be sufficient and additional risk
minimisation activities will be necessary.
V.B.11.2. RMP part V section “Additional risk minimisation activities”
Additional risk minimisation activities are those risk minimisation measures which are not the routine
risk minimisation activities listed above. Additional risk minimisation activities should only be
suggested when essential for the safe and effective use of the medicinal product and these should be
science based, and developed and provided by suitably qualified people. If additional risk minimisation
activities are proposed, these should be detailed and a justification of why they are needed provided.
Many additional risk minimisation tools are based on communication which aims to augment the
information in the summary of product characteristics (SmPC) and the package leaflet. Any
communication material should be clearly focused on the risk minimisation goals, and should not be
confused or combined with promotional material for marketing campaigns. Further description and
guidance on the use of additional risk minimisation activities is provided in Module XVI.
It is essential that appropriate specialists/ experts are involved when developing risk minimisation
activities. Marketing authorisation applicants/ holders are also encouraged to discuss risk minimisation
plans with the competent authorities as early as is feasible when it is likely that specific risk
minimisation activities will need to be adapted to the different health care systems in place in the
different Member States. For very complex risk minimisation measures, it may be appropriate to
contact competent authorities, in the countries where it is planned to market the product, either prior
to submitting risk minimisation proposals or during the course of the evaluation procedure. Where
possible and appropriate, proposed risk minimisation activities should be discussed with patients and
healthcare professionals if it is likely that risk minimisation activities will be directed towards them.
The Pharmacovigilance Risk Assessment Committee (PRAC) is the body mandated to review RMPs and
make recommendations on their content and on the suitability of proposed pharmacovigilance activities
and risk minimisation measures. For centrally authorised products, only additional risk minimisation
measures which are recommended by the PRAC and subsequently agreed by the CHMP will be allowed
in the risk minimisation plan and any other activities considered as not essential for the safe and
effective use of the product will need to be removed and an updated RMP submitted before the CHMP
Opinion. Additional risk minimisation activities will become, once agreed by the European Commission,
conditions of the marketing authorisation and the key elements will be detailed in annex II to the
Commission Decision and, exceptionally if applicable, a Commission Decision in accordance with the
annex 127a may be addressed to the Member States for implementation of certain of these
conditions.. Where appropriate, full details of additional risk minimisation activities (including mock
ups) should be provided in RMP annexes 10 and 11.
Educational material
Any educational material should be non-promotional. It is recommended that communication experts,
patients and healthcare professionals are consulted on the design and wording of educational material
and that, where appropriate, it is piloted before releasing for use.
For centrally authorised products, the CHMP will agree the key elements of what should be included in
the educational material and these key elements will become, once agreed by the European
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Commission, a condition of the marketing authorisation. The final version of the educational material
will need to be approved by the national competent authority for the territory in which it will be used
who will check that the material contains the key elements in an appropriate design and format and is
not promotional.
For public health reasons, applicants/marketing authorisation holders for the same active substance
may be required by the competent authority to have educational material with as similar as possible
layout, content, colour and format to avoid patient confusion. This requirement may also be extended
to other patient material such as patient alert cards and patient monitoring cards. For this reason,
marketing authorisation applicants/holder are strongly recommended to avoid the use of company
logos or other trademarked or patented material in educational material.
Further extensive guidance on additional risk minimisation measures is provided in Module XVI.
V.B.11.3. Format of risk minimisation plan(s)
Each safety concern identified in the summary of the safety specification should be addressed. If no
risk minimisation activity is proposed then “none proposed” should be entered against the objective.
For each safety concern, the following information should be provided:
• objectives of the risk minimisation activities
• routine risk minimisation activities;
• additional risk minimisation activities (if any), individual objectives and justification of why needed;
• how the effectiveness of each (or all) risk minimisation activities will be evaluated in terms of
attainment of their stated objectives;
• what the target is for risk minimisation, i.e. what are the criteria for judging success;
• milestones for evaluation and reporting.
For routine risk minimisation activities, the proposed text in the summary of product characteristics
(SmPC), or a précis, should be provided along with details of any other routine risk minimisation
activities proposed for that safety concern. If the medicinal product has two or more marketing
authorisations (i.e. in different Member States) which have different SmPC text, it may be appropriate
to comment on the differences in the text between Member States.
V.B.11.4. RMP part V section “Evaluation of the effectiveness of risk
minimisation activities”
Risk minimisation measures are public health interventions intended to prevent or reduce the
probability of the occurrence of adverse reactions associated with exposure to a medicinal product, or
to reduce their severity/impact on the patient should the adverse reactions occur. The terms "risk
minimisation measures and risk minimisation activities are used virtually synonymously in GVP. The
success of risk minimisation activities in delivering these objectives needs to be evaluated throughout
the lifecycle of a product to ensure that the burden of adverse reactions is minimised and hence the
overall risk-benefit balance is optimised.
When the RMP is updated, the risk minimisation plan should include an evaluation of the impact of
routine and/or additional risk minimisation activities as applicable. Such information may be presented
by region, if applicable/relevant. Results of any studies to assess the impact or other formal
assessment(s) of risk minimisation activities should be included when available. As part of this critical
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evaluation, the marketing authorisation holder should make observations on factors contributing to the
success or weakness of risk minimisation activities. If a particular risk minimisation strategy proves
ineffective, or to be causing an excessive or undue burden on patients or the healthcare system then
alternative activities need to be put in place. The marketing authorisation holder should always
comment on whether additional or different risk minimisation activities are needed for each safety
concern.
In certain cases it may be judged that risk minimisation cannot control the risks to the extent possible
to ensure a positive risk-benefit balance and that the medicinal product needs to be withdrawn either
from the market or restricted to those patients in whom the benefits outweigh the risks.
More extensive guidance on monitoring the effectiveness of risk minimisation activities is included in
Module XVI.
V.B.11.5. RMP part V section “Summary of risk minimisation measures”
A table summarising the routine and additional risk minimisation activities by safety concern should be
provided. This table will be used in the European Public Assessment Report (EPAR).
V.B.12. RMP part VI “Summary of activities in the risk management plan by
medicinal product”
A summary of the RMP for each medicinal product shall be made publically available [REG Art 23(3),
Art 26(c), DIR Art 106(c) IR Art 31(2)]. The summary must include key elements of the RMP with a
specific focus on risk minimisation activities. With regard to the safety specification of the medicinal
product concerned, it should contain important information on potential and identified risks as well as
missing information [IR Art 31(1)].
It is difficult for one summary to satisfy the needs of all stakeholders and there may be a need for a
summary of the RMP to be provided for different stakeholders in varying formats. For products
authorised under the centralised procedure, the Agency currently publishes a full scientific assessment
of the dossier in the format of a European Public Assessment Report (EPAR). This contains some
information on the RMP in an abbreviated tabular format since much of the relevant safety and efficacy
data is contained elsewhere within the EPAR. The Agency also publishes a brief summary of the EPAR
written in lay language (i.e. the EPAR summary).
Based on the information contained in part VI of the RMP, the Agency, in consultation with the national
competent authorities, have agreed three possible formats for the public summary of the RMP. These
take the form of the two documents described above (EPAR summary and information in the CHMP
assessment report in an abbreviated tabular format) and a more detailed summary of the RMP which is
published as a stand-alone document. There will be a stepwise implementation. Which format is used
for a particular medicine will depend upon the Member State and the type of product. The Agency is
piloting the publication of the detailed summary for centrally authorised products in addition to the two
documents described above.
The elements needed to fulfil these three documents are contained within Part VI of the RMP: “the
summary of the RMP” and are described in Sections V.B.12.1 to V.B.12.8.. This shall be provided for all
medicinal products which have a RMP regardless of whether they are centrally or nationally authorised.
The summary of the RMP shall be written by the MAA/MAH and will be evaluated during the
assessment of the RMP. The final format of the Summary and processes for its production and
publication are still subject to discussion. Further details will be published on the Agency website and
those of national competent authorities (as appropriate) as soon as these are available.
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V.B.12.1. RMP part VI section “format and content of the summary of the
RMP”
This is a scientific summary, written for the lay reader to fulfil the requirements in the legislation. In
situations where the RMP covers more than one product, a separate RMP part VI should be prepared
for each product. To present a balanced picture, the risks discussed in the RMP should be put into
context with a very concise and focussed description of the benefits of the medicinal product.
Technical terms, scientific abbreviations or acronyms should be avoided or explained in full if deemed
necessary.
The summary of the RMP part VI should contain the following information based on RMP modules SI,
SVIII and RMP parts IV and V:
• Overview of disease epidemiology;
• Summary of treatment benefits;
• Unknowns relating to treatment benefits;
• Summary of safety concerns:
- Important identified risks;
- Important potential risks;
- Missing information;
• Summary of risk minimisation activities by safety concern;
• Planned post authorisation development plan;
• Studies which are a condition of the marketing authorisation (see V.B.9.4. and V.B.10.2.);
• Major Changes to the Risk Management Plan over time.
The information provided in each section should be brief, focussed and in accordance with the word
limits in the templates.
V.B.12.2. RMP part VI section “Overview of disease epidemiology“
The applicant/marketing authorisation holder should summarise the epidemiology of the
disease/condition the medicinal product is intended to treat or prevent (as presented in RMP module
SI) in a non-alarmist manner and in language appropriate to the target population. If the product is
used in a range of disease severity, this fact should be emphasised and discussed. Sensitivity should
be used when presenting the morbidity and mortality of the disease whilst retaining factual accuracy.
If success of treatment is measured using survival figures, appropriate emphasis should be given to
the fact that, by definition, survival (e.g. 5 year survival) figures relate to historical treatment.
If the product is a diagnostic, product used for anaesthesia or similar usage not associated with a
particular disease/condition then this section of the overview may be omitted.
V.B.12.3. RMP part VI section “Summary of treatment benefits “
This should consist of very concise high level key messages concerning the results of the pivotal trials
and any important supplementary evidence and should adhere to the word limits in the template.
V.B.12.4. RMP part VI section “Unknowns relating to treatment benefits”
This should discuss the applicability of efficacy to all patients in the target population. It should
describe very briefly any relevant parts of the target population where experience is limited and
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whether efficacy is expected to be different in these people, e.g. factors such as age, sex, race and
organ impairment.
V.B.12.5. RMP part VI section “Summary of safety concerns”
This section should briefly describe the safety concerns in suitable language for the general public. It
should include the frequency and severity of the safety concern for the important identified risks and
their preventability.
Risk What is known Preventability
Risk 1
Risk 2 etc.
For important potential risks the reasons why the reason why it is thought to be a potential risk (e.g.
toxicology in animal study, known effect in other members of the pharmaceutical class) should be
explained together with the uncertainties, e.g. “occurs in other medicinal products in the same class
but was not seen in the clinical trials for this medicinal product which studied 3,761 people”.
Risk What is known
Risk 1
Risk 2 etc.
For missing information it should be stated (using the above format as well) that there is no, or
insufficient, information regarding the safety concern, the possible relevance to the target population
should be highlighted as well as the associated recommendations, e.g. contraindication, use with
caution.
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V.B.12.6. RMP part VI section “Summary of risk minimisation activities by
safety concern”
Details of routine risk minimisation measures will be provided in the published summary by a link to
the product information.
For each safety concern which has additional risk minimisation measures, brief details of the measures
for that concern should be provided. The objective and rationale for each measure should be stated
along with the proposed actions e.g.:
Where there are safety concerns specific to a particular indication or population, or where an ATMP is
involved it may be appropriate to structure the risks by the headings suggested in module SVII.
V.B.12.7. RMP part VI section “Planned post-authorisation development
plan”
Data should be presented in the form of a table showing the planned activities in terms of efficacy
studies and the further investigation of safety concerns. This table would combine the data from
sections V.B.9.4. and V.B.10.2.. Each row of the table should include the name of the study, objectives
for the study, the safety concern or efficacy issue being addressed, the status and planned date for
submission of the results.
List of studies in post authorisation development plan
Study Objectives Safety
concerns/efficacy
issue addressed
Status Planned
date for
submission
of (interim
and) final
results
Study 1
Study 2 etc
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Studies which are a condition of the marketing authorisation
Statement on which studies in the above table are conditions of the MA e.g. “None of the above studies
is a condition of the marketing authorisation.”
V.B.12.8. RMP part VI section “Summary of changes to the risk
management plan over time”
This table should provide a listing of all significant changes to the RMP in chronological order. This
should include, for example, the date and version number of the RMP when new safety concerns were
added or existing ones removed or changed, dates and version of the RMP when new studies were
added or finished, and a brief summary of changes to risk minimisation activities and the associated
dates these changes were agreed. Since changes to risk minimisation activities involve a variation, the
date used for changes to risk minimisation activities should be that of the decision, whether by the
European Commission or a national competent authority. The date for safety concerns and studies
should be the date of the RMP in which they are first added.
V.B.13. RMP part VII “Annexes to the risk management”
The RMP should contain the annexes listed below. Annexes 1-3, 10 and 11 should be provided for
each medicinal product within the RMP. If no information is available for a given annex this should be
stated. If a single study is addressing issues in both parts III and IV of the RMP, it should be included
in RMP annex 6 with a cross reference in RMP annex 8.
RMP annex 1: Interface between RMP and Eudravigilance/EPITT (electronic only)
See http://eudravigilance.ema.europa.eu/human/EURiskManagementPlans.asp.
RMP annex 2: Current (or proposed if product is not authorised) local (centralised/mutual
recognition/decentralised/national) summary of product characteristics (SmPC) and
package leaflet. If multiple versions are included, they should show in which
Member State(s) they are applicable. If available, a core SmPC should be provided
with an overview of the changes applicable to the SmPC in each Member State.
RMP annex 3: worldwide marketing authorisation status by country (including EEA). This should
include:
• current licence status (approved/refused/ under review/
suspended/expired/withdrawn);
• date(s) of approval/refusal/suspension/expiration/withdrawal;
• date(s) marketed/withdrawn from market;
• trade name(s);
• any explanatory comments.
RMP annex 4: Synopsis of on-going and completed clinical trial programme.
RMP annex 5: Synopsis of on-going and completed pharmacoepidemiological study programme.
RMP annex 6: Protocols for proposed and on-going studies in categories 1-3 of the section
“Summary table of additional pharmacovigilance activities” in RMP part III.
RMP annex 7: Specific adverse event follow-up forms.
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RMP annex 8: Protocols for proposed and on-going studies in RMP part IV.
RMP annex 9: Synopsis of newly available study reports for RMP parts III-IV.
RMP annex 10: Details of proposed additional risk minimisation activities (if applicable).
RMP annex 11: Mock up examples in English (or the National language if the product is only
authorised in a single Member State) of the material provided to healthcare
professionals and patients as a requirement of Annex II of the Commission Decision
or as a requirement of national authorisations including those using the mutual
recognition or decentralised procedure as applicable.
RMP annex 12: Other supporting data (including referenced material).
V.B.14. The relationship between the risk management plan and the
periodic safety update report
The primary post-authorisation pharmacovigilance documents will be the RMP and the periodic safety
update report (PSUR). Although there is some overlap between the documents, the main objectives of
the two are different and the situations when they are required are not always the same. Regarding
objectives, the main purpose of the PSUR is integrated, post-authorisation risk benefit assessment
whilst that of the RMP is pre-and post-authorisation risk-benefit management and planning. As such
the two documents are complementary. Regarding submission, whereas for many medicinal products,
both documents will need to be submitted, for other medicinal products only one will be required
depending upon where the product is in its lifecycle. For this reason both documents need to be
“stand-alone” but it is anticipated that certain modules may be common to prevent duplication of
effort.
The PSUR examines the overall safety profile as part of an integrated benefit-risk evaluation of the
medicinal product at set time periods and as such will consider the overall risk-benefit balance of the
medicinal product (and a much wider range of (suspected) adverse reactions). It is anticipated that
only a small proportion of these would be classified as important identified or important potential risks
and become a safety concern discussed within the RMP. Deciding to add an adverse reaction to section
4.8 of the summary of product characteristics (SmPC) is not a sufficient cause per se to include it as a
safety concern in the RMP (see V.B.8.7.2.).
When a PSUR and a RMP are to be submitted together, the RMP should reflect the conclusions of the
accompanying PSUR. For example if a new signal is discussed in the PSUR and the PSUR concludes
that this is an important identified or important potential risk, this risk should be included as a safety
concern in the updated RMP submitted with the PSUR. The pharmacovigilance plan and the risk
minimisation plan should be updated to reflect the marketing authorisation holder’s proposals to
further investigate the safety concern and minimise the risk.
V.B.14.1. Common modules between periodic safety update report and risk
management plan
The proposed PSUR and RMP modular format is intended to minimise duplication by enabling common
(sections of) modules to be utilised interchangeably across both reports. Common (sections of)
modules are identified in the following table.
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Table V.3: Common sections between RMP and PSUR (may not be in identical format)
RMP section PSUR section
Part II, module SV – “Post-authorisation
experience”, section “Regulatory and marketing
authorisation holder action for safety reason”
Section 3 – “Actions taken in the reporting
interval for safety reasons”
Part II, module SV – “Post-authorisation
experience”, section “Non-study post-
authorisation exposure”
Sub-section 5.2 – “Cumulative and interval
patient exposure from marketing experience”
Part II, Module SVII – “Identified and potential
risks”
Sub-section 16.4 – “Characterisation of risks”
Part II, module SVIII – “Summary of the safety
concerns” (as included in the version of the RMP
which was current at the beginning of the PSUR
reporting interval)
Sub-section 16.1 – “Summary of safety concerns”
Part V – “Risk minimisation measures”, section
“Evaluation of the effectiveness of risk
minimisation activities”
Sub-section 16.5 – “Effectiveness of risk
minimisation (if applicable)”
V.B.15. Principles for assessment of risk management plans
The principle points which need to be considered when preparing or reviewing a risk management plan
for a medicinal product are:
a. Safety specification
• Have all appropriate parts of the safety specification been included?
• Have all appropriate data been reviewed when compiling the safety specification, i.e. are there
important (outstanding) issues from other sections of the dossier which have not been discussed in
the safety specification?
• If parts of the target population have not been studied, have appropriate safety concerns in
relation to potential risks and missing information been included?
• What are the limitations of the safety database and what reassurance does it provide regarding the
safety profile of the medicinal product?
• Are there specific risks in addition to those addressed under ICH-E2E, e.g. off-label use, misuse
and abuse, transmission of infectious disease, medication error, etc.?
• Does the safety specification provide a true reflection of the safety concerns (i.e. important
identified risks, important potential risks and missing information) with the product?
• If a generic or hybrid application, have all safety concerns from the reference medicinal product
been included in the safety specification?
• Does its place in the therapeutic armamentarium as described concur with the intended indication
and current medical practice?
b. Pharmacovigilance plan
• Are all safety concerns from the safety specification covered in the pharmacovigilance plan?
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• Are routine pharmacovigilance activities adequate or are additional pharmacovigilance activities
necessary?
• Are the activities in the pharmacovigilance plan clearly defined and described and suitable for
identifying or characterising risks or providing missing information?
• Are the safety studies which have been imposed by a competent authority as conditions clearly
identified?
• If medication error is a safety concern, does the RMP include appropriate proposals to monitor
these?
• Are the proposed additional studies necessary and/or useful?
• When draft protocols are provided, are the proposed studies in the pharmacovigilance plan
adequate to address the scientific questions and are the studies feasible?
• Are appropriate timelines and milestones defined for the proposed actions, the submission of their
results and the updating of the pharmacovigilance plan?
c. Plans for post-authorisation studies on efficacy
• Does the description of the efficacy of the product and what studies and endpoints it was based on
conform with the contents of the dossier?
• Do all proposed studies have a valid scientific question as their primary aim and are any designed
to increase use of the product)?
d. Risk minimisation measures
• Does the product information adequately reflect all important identified risks and missing
information?
• Are any potential risks sufficiently relevant to the safe and effective use of the product that
information about them should be included in the product information?
• Is the proposed wording about the risks and location in the product information appropriate and in
line with relevant guidelines (e.g. SmPC guideline)?
• Has the marketing authorisation holder considered ways to reduce medication errors?
• Has this been translated into appropriate product information (including device design where
appropriate) and pack design?
• Are proposed risk minimisation activities appropriate and adequate?
• Have additional risk minimisation activities been suggested and if so, are they risk proportionate
and adequately justified?
• Are the methodologies for measuring and assessing the effectiveness of risk minimisation activities
well described and appropriate?
• Have criteria for evaluating the success of additional risk minimisation activities been defined a
priori?
e. Summary of the Risk Management Plan
• Is it a true representation of the RMP?
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• Have the facts been presented appropriately
• Are the content, format and language suitable for the intended audience?
• Have all required formats been provided?
f. When an update is being assessed
• Have new data been incorporated into the safety specification?
• Have appropriate changes been made to the pharmacovigilance plan (if necessary in the light of
new data)?
• Is there an evaluation of the effectiveness of risk minimisation measures?
• Have appropriate changes to risk minimisation measures been proposed if necessary?
• Does the new data suggest that a formal evaluation of the risk-benefit balance (if not already done
in a PSUR) is needed?
V.B.16. Quality systems and record management
Although many experts may be involved in writing the RMP, the final responsibility for its quality,
accuracy and scientific integrity lies with the marketing authorisation applicant/holder. As such the
qualified person responsible for pharmacovigilance in the EU (QPPV) should be aware of, and have
sufficient authority over the content. The marketing authorisation holder is responsible for updating the
RMP when new information becomes available and should apply the quality principles detailed in
Module I. The marketing authorisation holder should maintain records of when RMPs were submitted to
EU competent authorities and the significant changes between each version of the RMP. These records,
the RMPs and any documents relating to information within the RMP may be subject to audit and
inspection by appropriately qualified pharmacovigilance inspectors.
V.C. Operation of the EU network
Risk management in the EU has historically focused upon the risk reduction approach. In the EU, the
legislation uses the terms “risk management system” and “risk management plan.” The chapter on risk
management systems for medicinal products for human use in Volume 9A, which this guidance
replaces, was based solely on managing risks. However, when considering how to maximise, or indeed
assess, the risk-benefit balance, risks need to be understood in the context of benefit.
V.C.1. Legal basis for the implementation of risk management within the EU
Directive 2001/83/EC and Regulation (EC) No 726/2004 as amended contain many requirements in
relation to pharmacovigilance and in particular risk management. The following articles provide the
main references in relation to the legal basis for risk management but additional articles may also be
relevant:
Directive 2001/83/EC
Article 8 (3), Article 21a, Article 22a, Article 22c, Article 104, Article 106(c), Article 127a
Commission Implementing Regulation (EU) No. 520/512
Article 30, Article 31, Article 32, Articles 33, Annex 1
Regulation (EC) No 726/2004
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Article 6, Article 9(4), Article 10a, Articles 23(3), Article 26(c)
Regulation (EC) No 1901/2006
Article 34
Regulation (EC) No 1394/2007
Article 14
V.C.2. Risk management in the EU
As stated above, the overall aim of risk management is to ensure that the benefits of a particular
medicinal product (or a series of medicinal products) exceed the risks by the greatest achievable
margin for the individual patient and for the target population as a whole. Therefore, although the legal
provisions primarily relate to risks, public health will be better served by looking at both benefits and
risks. Regulation (EU) No 1235/2010 amending Regulation (EC) No 726/2004 and Directive
2010/84/EU amending Directive 2001/83/EC, which apply from July 2012, include provisions for post-
authorisation efficacy studies, in addition to post-authorisation safety studies, to be a condition of the
marketing authorisation in certain circumstances.
The requirements in the Directive and Regulation are linked to medicinal products. However, to
prevent duplication of planning and resource utilisation, the Commission Implementing Regulation on
the Performance of Pharmacovigilance Activities Provided for in Regulation (EC) No 726/2004 and
Directive 2001/83/EC provides the possibility for risk management plans to be substance specific. For
an individual marketing authorisation holder and applicant, all products containing the same active
substance should be included in one RMP [IR Art 30(2)] unless separate presentations are requested
by the competent authority or agreed by the same at the request of the applicant/marketing
authorisation holder. If the marketing authorisation holder has products in the same substance class
authorised under different authorisation routes (i.e. centralised, decentralised), the competent
authorities should be notified of this fact and the need for separate RMPs discussed with them.
Pragmatic and practical considerations should determine the need for united or separated RMPs.
V.C.3. Situations when a risk management plan should be submitted
An RMP or an update, as applicable, may need to be submitted at any time during a product’s life-
cycle, i.e. during both the pre- and post-authorisation phases.
Article 8(3)(iaa) requires that for all new marketing applications: the risk management plan describing
the risk management system which the applicant will introduce for the medicinal product concerned
shall be submitted, together with a summary thereof.
Situations, in addition, where a RMP or RMP update will normally be expected include:
• with an application involving a significant change to an existing marketing authorisation:
− new dosage form;
− new route of administration;
− new manufacturing process of a biotechnologically-derived product;
− paediatric indication;
− other significant change in indication;
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A significant change in indication is a change of authorised indication(s) of a medicinal product
where the new treatment target population differs materially from the one for which the
medicinal product was previously authorised. This includes (but is not limited to): a new
disease area, a new age group (e.g. paediatric indication) or a move from severe disease to a
less severely affected population. It may also include a move from 2nd line or other therapy or
for an oncology product a change to the concomitant medication specified in the indication.
• at the request of the Agency or national competent authority when there is a concern about a risk
affecting the risk-benefit balance;
• with a submission of final study results impacting the RMP;
• with a PSUR for single centrally authorised medicinal product, when the changes to the RMP are a
direct result of data presented in the PSUR.
The need for a RMP or an update to the RMP should be discussed with the Agency or national
competent authority, as appropriate, well in advance of the submission of an application involving a
significant change to an existing marketing authorisation.
An updated RMP should always be submitted if there is a significant change to the risk-benefit balance
of one or more medicinal products included in the RMP.
V.C.3.1. Requirements in specific situations
Normally all parts of an RMP should be submitted. However, in certain circumstances as detailed
below, in line with the concept of proportionality, certain parts or modules may be omitted (see Figure
V.3) unless otherwise requested by the competent authority. However, any safety concerns identified
in a reference medicinal product in a module which is omitted from the risk management plan of a
generic should be included in RMP module SVIII unless clearly no longer relevant.
a. New applications involving generic medicinal products
For new applications under Article 10(1) of Directive 2001/83/EC, RMP modules SI – SVII may be
omitted. RMP module SVIII should be based on the safety concerns of the reference medicinal product
unless the generic differs significantly in properties which could relate to safety, or unless requested
otherwise by the Agency or national competent authority. Provided the reference medicinal product
does not have any additional pharmacovigilance activities or efficacy studies imposed as a condition of
the marketing authorisation, RMP parts III and IV may be omitted. Part VI should be based on an
appropriately modified version of the public summary of the reference medicinal product.
Further guidance will be provided for situations where the reference medicinal product does not have a
RMP.
For updates to the RMP, RMP module SV should be included.
b. New applications under Article 10c “informed consent”
For new applications under Article 10c of Directive 2001/83/EC, the RMP should be the same as the
RMP of the cross-referred medicinal product. A RMP will still be required even if the cross-referred
product does not have a RMP.
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c. New applications involving hybrid or fixed combination medicinal products
For new applications under Article 10(3) or Article 10b of Directive 2001/83/EC, only the data on the
fixed combination or data relating to the differences compared with the reference medicinal product
need be supplied for RMP modules SII and SIII.
d. New applications under Article 10a “well established medicinal use”
For new applications under Article 10a of Directive 2001/83/EC, RMP modules SII - SIV may be
omitted.
e. New applications for a product with new indications where the marketing authorisation
applicant already has products with the same active substance authorised for 10 years
When an application for a new medicinal product, is for the same active substance for which the
marketing authorisation applicant already has one or more existing authorised and marketed
product(s) and
1. the provisions of “well established medicinal use” cannot be met; and
2. the marketing authorisation applicant does not have a risk management plan for any product
containing the active substance; and
3. the currently authorised products were placed on the market in the EU 10 or more years prior to
the application.
Clinical trial data relating to the already authorised product(s) may be omitted from RMP module SIII
and RMP module SIV should be written only in reference to the target population(s) of the new
application unless requested otherwise by the competent authority. However, data from experience of
the use of the already authorised medicinal products in the special populations which are the subject of
RMP module SIV may be included.
Figure V.3. Requirements for new marketing applications
Type of new application
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New active substance � � � � � � � � � � � � � �
Similar biological � � � � � � � � � � � � �
Informed consent1 � � � � � � � � � ∗ ∗ � ∗ �
Generic medicine � � ∗ ∗ � ∗ �
Hybrid medicinal products � � ^ ^ � � � � � � � � � �
Fixed combination � � ^ ^ � � � � � � � � � �
“Well established use” � � � � � � � � � � �
“Same active substance” � � ∗ ∗ ∗ � � � � � � � � �
1 Application under Article 10(c) of Directive 2001/83/EC
^ May be omitted under certain circumstances
∗ Modified requirement
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f. Initial risk management plan for medicinal products on the market in the EU for 10 years
Unless otherwise requested by the Agency or competent authority, marketing authorisation holders
required to submit an initial RMP for a marketed product may omit modules SIII and SIV provided the
following conditions are met:
1. the product was placed on the market 10 or more years before the requirement for an RMP is
established; and
2. the requirement for an RMP is not due to an application for a significant change to an existing
marketing authorisation.
If condition 2 cannot be met, clinical trial data relating to this change should be supplied in RMP
module SIII but RMP module SIV may be omitted. Discussion of the existing post-authorisation data
and its applicability to the target population should be extensively discussed in RMP module SV.
V.C.4. Submission of the risk management plan
Currently, for centrally authorised products, the RMP is submitted as PDF files within the eCTD
submission. Following a Commission Decision where the procedure has involved the submission of an
RMP, marketing authorisation holders submit the RMP annex I in XML format within a specified
timescale. RMP annex I provides the key information regarding the RMP in a structured electronic
format which, following validation at the Agency, is uploaded into an Agency database which is
accessible and searchable by the Agency and national competent authorities. The system for nationally
authorised products varies by Member State.
The Agency is charged with setting up and maintaining a repository for PSURs in collaboration with
competent authorities in Member States and the European Commission (see Module VII). It is
anticipated that this will contain an RMP module. In the interim period, details of submission
requirements and the electronic format will be provided on the Agency and Member State websites as
appropriate.
The initial RMP should be submitted as part of the initial marketing authorisation, or if required, for
those products that do not have an RMP, through the appropriate post-authorisation procedure.
Post-authorisation, submission of a new or updated RMP outside of another regulatory procedure
constitutes a variation in accordance with the Guidelines on Variations14. For detailed guidance on
relevant variation categories and their classification, please also refer to the Agency’s Practical
Questions and Answers to support the implementation of the Guidelines on Variations in the centralised
procedure.
V.C.5. Updates to the risk management plan
If an RMP has previously been submitted by the applicant/marketing authorisation holder for the active
substance, any following submissions shall be in the form of an update unless requested otherwise.
Each submission of the RMP shall have a distinct version number and shall be dated. This applies
whether the entire RMP or only a part or module is being submitted [IR Art 32(2)]. When technically
14 Guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters
II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of
variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products
and on the documentation to be submitted pursuant to those procedures.
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feasible, clean and track change versions should be submitted along with a cover letter detailing the
changes since the last submitted version.
There will no longer be scheduled “routine” updates to the RMP. In exceptional cases, when justified by
risk, the competent authority may still specify a date for submission of the next RMP as a condition of
the marketing authorisation.
It is the responsibility of the marketing authorisation holder to monitor the safety profile of the
product(s) and to update and submit the RMP if there is a significant change to the risk-benefit balance
of one or more medicinal products included in the RMP. A significant change would, in particular,
usually include extension of indications, clinically important changes to the product information,
reaching an important pharmacovigilance milestone and also certain new strengths and formulations.
An updated RMP should now be submitted:
• at the request of the Agency or a national competent authority;
• whenever the risk management system is modified, especially as the result of new information
being received that may lead to a significant change to the risk-benefit balance or as a result of an
important pharmacovigilance or risk minimisation milestone being reached.
If, when preparing a PSUR, there is a need for consequential changes to the RMP as a result of new
safety concerns, or other data, then an updated RMP should be submitted at the same time. In this
case no stand-alone RMP variation is necessary.
Should only the timing for submission of both documents coincide, but the changes are not related to
each other, the RMP submission should be handled as a stand-alone variation.
However, in the context of a PSUR EU single assessment (PSUSA), as an interim measure, submission
of RMP updates cannot be accepted together with the PSURs of medicinal products (centrally and/or
nationally authorised). Marketing authorisation holders should take the opportunity of another
upcoming procedure to update their RMP. Alternatively marketing authorisation holders should submit
a separate variation to update their RMP. (See also Practical questions and answers to support the
implementation of the variations guidelines in the centralised procedure15).
For nationally authorised medicinal products, RMP updates should be submitted to the national
competent authority for assessment.
When the RMP is updated, the risk minimisation plan should include an evaluation of the impact of
routine and/or additional risk minimisation activities as applicable (see V.B.11.4.).
V.C.5.1. Updates to the risk management plan submitted during a
procedure
A medicinal product can only have one “current” version of a RMP. If a medicinal product has more
than one procedure in process at the same time which requires submission of a RMP, ideally a
combined RMP should be submitted with appropriate separation of data in RMP module SIII. In certain
circumstances, when this is not possible or practical, there may be more than one version of the RMP
under evaluation at a time.
If several updates to the RMP are submitted during the course of a procedure, the version considered
as the “current” RMP for future updates and track changes purposes, shall be the last one submitted
15
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000104.jsp&mid=WC
0b01ac0580025b88
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before the Opinion. For example, in the final weeks before the Opinion, the RMP may be updated
several times to reflect on-going PRAC and CHMP discussions, e.g. changed indications, changes in
SmPC wording which affect risk minimisation.
Following the finalisation of the procedure, the final version of the RMP should be provided in eCTD.
For centrally authorised procedures, the final RMP agreed at the time of the CHMP Opinion should also
be provided as a word document within 15 days of the Opinion. The RMP should reflect the outcome of
the procedure – i.e. removal of all references and data which were subject to a negative Opinion. The
exception to this requirement is that populations studied in clinical trials related to a negative Opinion
may be included in suitably annotated exposure data in RMP module SIII.
Unless requested otherwise, for RMPs updated during (after the start) of a procedure, track changes
should show changes since the start of the procedure whilst the cover letter should show changes since
the last version was submitted.
V.C.6. Procedure for the assessment of the risk management plan within
the EU
Within the EU, the regulatory oversight of RMPs for products authorised either centrally or in more
than one Member State lies with the Pharmacovigilance Risk Assessment Committee (PRAC). The PRAC
appoints a PRAC rapporteur for an individual RMP who works closely with the (Co-)Rapporteur(s)
appointed by the CHMP or with the Reference Member State. Further guidance on the details of the
process will be added later.
The EMA may, on a case-by-case basis, consult with healthcare professionals and patients during the
assessment of RMPs to gather their input on proposed risk minimisation measures.
V.C.7. Implementation of additional risk minimisation activities for
centrally authorised products
Centrally authorised products have one marketing authorisation for the whole of the EU. However,
individual Member States may have very different health systems and medical practice may differ
between Member States so the conditions and restrictions in the marketing authorisation may be
implemented in different ways depending upon national customs. For this reason there will be two
Commission Decisions – one addressed to the marketing authorisation holder describing the key
elements of any conditions and/or restrictions that the marketing authorisation holder must
implement, and one addressed to the Member States giving the Member States the responsibility for
ensuring that the key elements described in the conditions and/or restrictions are implemented by the
marketing authorisation holder in their territory. How these key elements are implemented in each
Member State is a matter for discussion and agreement between the national competent authority and
the marketing authorisation holder. For centrally authorised products which are likely to require major
risk minimisation activities, marketing authorisation holders are encouraged to discuss the feasibility of
how they might be implemented with individual national competent authorities during the building of
the risk minimisation plan.
For products with additional risk minimisation activities, it is the responsibility of the marketing
authorisation holder and national competent authority to ensure that all conditions or restrictions with
regard to the safe use of the product are complied with prior to the launch of the product in a
particular territory.
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Marketing authorisation holders are responsible for ensuring compliance with the conditions of the
marketing authorisation for their product wherever it is used within the European Economic Area
(EEA).
National competent authorities should also ensure that any conditions or restrictions with regard to the
safe and effective use of a centrally authorised product are applied within their territory regardless of
the source of the product.
V.C.8. Transparency
The Agency and Member States shall make publically available public assessment reports and
summaries of risk management plans [REG Art 26(1), DIR Art 106].
For centrally authorised products the Agency will:
• make public a summary of the RMP;
• include tables relating to the RMP in the European Public Assessment Report (EPAR) including the
product information and any conditions of the marketing authorisation.
To promote public health, the Agency will make available (either on request or via its web portal):
• any questionnaires included in RMPs for centrally authorised products which are used to collect
information on specified adverse reactions;
• details, which may include copies, of educational material or other additional risk minimisation
activities required as a condition of the marketing authorisation;
• details of disease or substance registries requested as part of the pharmacovigilance plan for
centrally authorised products.
The national competent authorities will provide details of how they intend to implement Article 106 of
Directive 2001/83/EC.
29.07.2014
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See websites for contact details
European Medicines Agency www.ema.europa.eu
Heads of Medicines Agencies www.hma.eu
The European Medicines Agency is
an agency of the European Union
© European Medicines Agency and Heads of Medicines Agencies, 2012.
Reproduction is authorised provided the source is acknowledged.
22 June 2012
EMA/873138/2011
Guideline on good pharmacovigilance practices (GVP)
Module VI – Management and reporting of adverse reactions to medicinal
products
Draft finalised by the agency in collaboration with Member States and submitted
to ERMS FG
19 January 2012
Draft agreed by ERMS FG 24 January 2012
Draft adopted by Executive Director 20 February 2012
Released for consultation 21 February 2012
End of consultation (deadline for comments) 18 April 2012
Revised draft finalised by the Agency in collaboration with Member States 20 June 2012
Revised draft agreed by ERMS FG 21 June 2012
Revised draft adopted by Executive Director as final 22 June 2012
Date for coming into effect 2 July 2012
Guideline on good pharmacovigilance practices (GVP) – Module VI
EMA/873138/2011 Page 2/90
TABLE OF CONTENTS
VI.A. Introduction ....................................................................................... 5
VI.A.1. Scope ............................................................................................................. 5
VI.A.2. Definitions ....................................................................................................... 5
VI.A.2.1. Adverse reaction ........................................................................................... 5
VI.A.2.1.1. Causality ................................................................................................... 5
VI.A.2.1.2. Overdose, off-label use, misuse, abuse, occupational exposure ........................ 6
VI.A.2.2. Medicinal product .......................................................................................... 6
VI.A.2.3. Primary source .............................................................................................. 7
VI.A.2.4 Seriousness ................................................................................................... 7
VI.A.2.5. Individual Case Safety Report (ICSR) ............................................................... 8
VI.B. Structures and Processes ................................................................... 9
VI.B.1. Collection of reports ......................................................................................... 9
VI.B.1.1. Unsolicited reports ......................................................................................... 9
VI.B.1.1.1. Spontaneous reports ................................................................................... 9
VI.B.1.1.2. Literature reports ..................................................................................... 10
VI.B.1.1.3. Reports from other sources ........................................................................ 10
VI.B.1.1.4. Information on suspected adverse reactions from the internet or digital media . 10
VI.B.1.2. Solicited reports .......................................................................................... 11
VI.B.2. Validation of reports ....................................................................................... 11
VI.B.3. Follow-up of reports ....................................................................................... 13
VI.B.4. Data management ......................................................................................... 13
VI.B.5. Quality management ...................................................................................... 14
VI.B.6. Special situations ........................................................................................... 15
VI.B.6.1. Use of a medicinal product during pregnancy or breastfeeding .......................... 15
VI.B.6.2. Use of a medicinal product in a paediatric or elderly population ......................... 16
VI.B.6.3. Reports of overdose, abuse, off-label use, misuse, medication error or occupational
exposure ................................................................................................................. 16
VI.B.6.4. Lack of therapeutic efficacy .......................................................................... 16
VI.B.7. Reporting of ICSRs ......................................................................................... 17
VI.B.7.1. Reporting time frames ................................................................................. 17
VI.B.8. Reporting modalities ....................................................................................... 18
VI.C. Operation of the EU Network ............................................................ 19
VI.C.1. Interface with safety reporting rules for clinical trials and post authorisation studies
in the EU ................................................................................................................. 19
VI.C.1.1. Interface with clinical trials ........................................................................... 20
VI.C.1.2. Interface with post-authorisation studies ........................................................ 21
VI.C.1.2.1. Non-interventional studies ......................................................................... 22
VI.C.1.2.2. Compassionate use, named patient use ....................................................... 22
VI.C.2. Collection of reports ....................................................................................... 23
VI.C.2.1. Member States responsibilities ...................................................................... 23
VI.C.2.2. Marketing authorisation holders responsibilities ............................................... 24
VI.C.2.2.1. Spontaneous reports ................................................................................. 25
VI.C.2.2.2. Solicited reports ....................................................................................... 25
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VI.C.2.2.3. Case reports published in the scientific and medical literature ........................ 25
VI.C.2.2.4. Suspected adverse reactions related to quality defect or falsified medicinal
products .................................................................................................................. 26
VI.C.2.2.5. Suspected transmission via a medicinal product of an infectious agent ............ 27
VI.C.2.2.6. Emerging safety issues .............................................................................. 27
VI.C.2.2.7. Period between the submission of the marketing authorisation application and
the granting of the marketing authorisation ................................................................. 28
VI.C.2.2.8. Period after suspension, revocation or withdrawal of marketing authorisation .. 29
VI.C.2.2.9. Period during a public health emergency ..................................................... 29
VI.C.2.2.10. Reports from class action lawsuits ............................................................ 29
VI.C.2.2.11. Reports from patient support programmes and market research programmes 29
VI.C.3. Reporting time frames .................................................................................... 30
VI.C.4. Reporting modalities ....................................................................................... 30
VI.C.4.1. Interim arrangements .................................................................................. 30
VI.C.4.2. Final arrangements ...................................................................................... 31
VI.C.5. Collaboration with the World Health Organization and the European Monitoring
Centre for Drugs and Drug Addiction ........................................................................... 32
VI.C.6. Electronic exchange of safety information in the EU ............................................ 32
VI.C.6.1. Applicable guidelines, definitions, international formats, standards and
terminologies ........................................................................................................... 32
VI.C.6.2. Electronic Reporting of Individual Case Safety Reports ..................................... 33
VI.C.6.2.1. EudraVigilance Database Modules ............................................................... 33
VI.C.6.2.1.1. Adverse reaction data collected in the EudraVigilance Post-Authorisation
Module .................................................................................................................... 33
VI.C.6.2.1.2. Adverse Reaction Data Collected in the EudraVigilance Clinical Trial Module .. 34
VI.C.6.2.2. Preparation of Individual Case Safety Reports .............................................. 34
VI.C.6.2.2.1. General principles .................................................................................. 34
VI.C.6.2.2.2. Information on suspect, interacting and concomitant medicinal products ...... 35
VI.C.6.2.2.3. Suspected adverse reactions ................................................................... 36
VI.C.6.2.2.4. Case narrative, causality assessment and comments .................................. 37
VI.C.6.2.2.5. Test results ........................................................................................... 38
VI.C.6.2.2.6. Supplementary information ..................................................................... 38
VI.C.6.2.2.7. Follow-up information ............................................................................. 38
VI.C.6.2.2.8. What to take into account for data privacy laws ......................................... 40
VI.C.6.2.2.9. Handling of languages ............................................................................ 40
VI.C.6.2.2.10. Nullification of cases ............................................................................. 40
VI.C.6.2.3. Special situations ..................................................................................... 41
VI.C.6.2.3.1. Use of a medicinal product during pregnancy or breastfeeding .................... 41
VI.C.6.2.3.2. Suspected adverse reaction reports published in the scientific and medical
literature ................................................................................................................. 41
VI.C.6.2.3.3. Suspected adverse reactions related to overdose, abuse, off-label use, misuse,
medication error or occupational exposure ................................................................... 42
VI.C.6.2.3.4. Lack of therapeutic efficacy ..................................................................... 42
VI.C.6.2.3.5. Suspected adverse reactions related to quality defect or falsified medicinal
products .................................................................................................................. 43
VI.C.6.2.3.6. Suspected transmission via a medicinal product of an infectious agent ......... 43
VI.C.6.2.3.7. Reports originating from organised data collection systems and other systems
.............................................................................................................................. 43
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VI.C.6.2.3.8. Receipt of missing minimum information .................................................. 44
VI.C.6.2.4. Data quality of individual case safety reports transmitted electronically and
duplicate management .............................................................................................. 45
VI.C.6.2.5. Electronic re-transmission of ICSRs between multiple senders and receivers .... 46
VI.C.6.2.6. Electronic reporting through company’s headquarters ................................... 46
VI.C.6.3. Electronic submission of information on medicinal products .............................. 47
VI. Appendix 1 Identification of biological medicinal products .................. 48
VI. Appendix 2 Detailed guidance on the monitoring of scientific and
medical literature ...................................................................................... 51
VI. App2.1 When to start and stop searching in the scientific and medical literature .......... 51
VI. App2.2 Where to look ........................................................................................... 51
VI. App2.3 Database Searches ................................................................................... 52
VI. App2.3.1 Precision and recall................................................................................. 52
VI. App2.3.2 Search construction ................................................................................ 52
VI. App2.3.3 Selection of product terms ...................................................................... 52
VI. App2.3.4 Selection of search terms ........................................................................ 53
VI. App2.3.5 Limits to a search ................................................................................... 53
VI. App2.4 Record keeping ......................................................................................... 54
VI. App2.5 Outputs ................................................................................................... 54
VI. App2.6 Review and selection of articles .................................................................. 54
VI. App2.7 Day zero .................................................................................................. 55
VI. App2.8 Duplicates ................................................................................................ 55
VI. App2.9 Contracting out Literature Search Services ................................................... 55
VI. App2.10 Electronic submission of copies of articles published in the scientific and medical
literature ................................................................................................................. 55
VI. Appendix 3 Modalities for reporting ..................................................... 60
VI. Appendix 3.1 Interim arrangements ....................................................................... 60
VI. Appendix 3.1.1 Interim arrangements applicable to marketing authorisation holders .... 66
VI. Appendix 3.1.2 Interim arrangements applicable to competent authorities in Member
States ..................................................................................................................... 67
VI. Appendix 3.2 Final arrangements ........................................................................... 68
VI. Appendix 3.2.1 Final arrangements applicable to marketing authorisation holders ........ 71
VI. Appendix 3.2.2 Final arrangements applicable to competent authorities in Member States
.............................................................................................................................. 71
VI. Appendix 3.3 Transmission and rerouting of ICSRs to competent authorities in Member
States .................................................................................................................... 72
VI. Appendix 4 Transmission of ICSRs to World Health Organisation (WHO)
.................................................................................................................. 76
VI. Appendix 5 Nullification of cases ......................................................... 80
VI. Appendix 6 Data quality monitoring of ICSRs transmitted electronically
.................................................................................................................. 84
VI. Appendix 7 Duplicate detection and management of ICSRs ................. 87
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VI.A. Introduction
VI.A.1. Scope
This Module addresses the legal requirements detailed in Title IX of Directive 2001/83/EC [DIR] and
Chapter 3 of Regulation (EC) No 726/2004 [REG], which are applicable to competent authorities in
Member States, marketing authorisation holders and the Agency as regards the collection, data
management and reporting of suspected adverse reactions (serious and non-serious) associated with
medicinal products for human use authorised in the European Union (EU). Recommendations regarding
the reporting of emerging safety issues or of suspected adverse reactions occurring in special
situations are also presented in this Module. The requirements provided in Chapter IV, V and IX of the
Commission Implementing Regulation (EU) No 520/2012 [IR] shall be applied in this Module.
The guidance provided in this Module does not address the collection, management and reporting of
events or patterns of use, which do not result in suspected adverse reactions (e.g. asymptomatic
overdose, abuse, off-label use, misuse or medication error) or which do not require to be reported as
individual case safety report or as Emerging Safety Issues. This information may however need to be
collected and presented in periodic safety update reports for the interpretation of safety data or for the
benefit risk evaluation of medicinal products. In this aspect, guidance provided in Module VII applies.
All applicable legal requirements detailed in this Module are referenced in the way explained in the GVP
Introductory Cover Note and are usually identifiable by the modal verb “shall”. Guidance for the
implementation of legal requirements is provided using the modal verb “should”.
VI.A.2. Definitions
The definitions provided in Article 1 of Directive 2001/83/EC shall be applied for the purpose of this
Module; of particular relevance are those provided in this chapter. Some general principles presented
in the ICH-E2A and ICH-E2D guidelines1 should also be adhered to; they are included as well in this
chapter.
VI.A.2.1. Adverse reaction
An adverse reaction is a response to a medicinal product which is noxious and unintended [DIR Art 1].
This includes adverse reactions which arise from:
• the use of a medicinal product within the terms of the marketing authorisation;
• the use outside the terms of the marketing authorisation, including overdose, off-label use,
misuse, abuse and medication errors;
• occupational exposure.
VI.A.2.1.1. Causality
In accordance with the ICH-E2A guideline, the definition of an adverse reaction implies at least a
reasonable possibility of a causal relationship between a suspected medicinal product and an adverse
event. An adverse reaction, in contrast to an adverse event, is characterised by the fact that a causal
relationship between a medicinal product and an occurrence is suspected. For regulatory reporting
purposes, as detailed in the ICH-E2D guideline, if an event is spontaneously reported, even if the
1 http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html
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relationship is unknown or unstated, it meets the definition of an adverse reaction. Therefore all
spontaneous reports notified by healthcare professionals, patients or consumers are considered
suspected adverse reactions, since they convey the suspicions of the primary sources, unless the
reporters specifically state that they believe the events to be unrelated or that a causal relationship
can be excluded.
VI.A.2.1.2. Overdose, off-label use, misuse, abuse, occupational exposure
a. Overdose
This refers to the administration of a quantity of a medicinal product given per administration or
cumulatively, which is above the maximum recommended dose according to the authorised product
information. Clinical judgement should always be applied.
b. Off-label use
This relates to situations where the medicinal product is intentionally used for a medical purpose not in
accordance with the authorised product information.
c. Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used not in
accordance with the authorised product information.
d. Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which
is accompanied by harmful physical or psychological effects [DIR Art 1].
e. Occupational exposure
This refers to the exposure to a medicinal product (as defined in [DIR Art 1]), as a result of one’s
professional or non-professional occupation.
VI.A.2.2. Medicinal product
A medicinal product is characterised by any substance or combination of substances,
• presented as having properties for treating or preventing disease in human beings; or
• which may be used in or administered to human beings either with a view to restoring, correcting
or modifying physiological functions by exerting a pharmacological, immunological or metabolic
action, or to making a medical diagnosis [DIR Art 1].
In accordance with Article 107 of Directive 2001/83/EC, the scope of this module is not only applicable
to medicinal products authorised in the EU but also to any such medicinal products commercialised
outside the EU by the same marketing authorisation holder (see VI.C.2.2). Given that a medicinal
product is authorised with a defined composition, all the adverse reactions suspected to be related to
any of the active substances being part of a medicinal product authorised in the EU should be managed
in accordance with the requirements presented in this module. This is valid independently of the
strengths, pharmaceutical forms, routes of administration, presentations, authorised indications, or
trade names of the medicinal product.
The guidance provided in this Module also applies, subject to amendments where appropriate, to
medicinal products supplied in the context of compassionate use (see VI.C.1.2.2) as defined in Article
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83(2) of Regulation (EC) No 726/2004. As the case may be, this guidance may also apply to named
patient use as defined under Article 5(1) of Directive 2001/83/EC.
VI.A.2.3. Primary source
The primary source of the information on a suspected adverse reaction(s) is the person who reports
the facts. Several primary sources, such as healthcare professionals and/or a consumer, may provide
information on the same case. In this situation, all the primary sources’ details, including the
qualifications, should be provided in the case report, with the “Primary source(s)” section repeated as
necessary in line with the ICH-E2B(R2) guideline2.
In accordance with the ICH-E2D guideline,
• a healthcare professional is defined as a medically-qualified person such as a physician, dentist,
pharmacist, nurse, coroner or as otherwise specified by local regulations;
• a consumer is defined as a person who is not a healthcare professional such as a patient, lawyer,
friend, relative of a patient or carer.
Medical documentations (e.g. laboratory or other test data) provided by a consumer that support the
occurrence of the suspected adverse reaction, or which indicate that an identifiable healthcare
professional suspects a reasonable possibility of causal relationship between a medicinal product and
the reported adverse event, are sufficient to consider the spontaneous report as confirmed by a
healthcare professional.
If a consumer initially reports more than one reaction and at least one receives medical confirmation,
the whole report should be documented as a spontaneous report confirmed by a healthcare
professional and be reported accordingly. Similarly, if a report is submitted by a medically qualified
patient, friend, relative of the patient or carer, the case should also be considered as a spontaneous
report confirmed by a healthcare professional.
VI.A.2.4 Seriousness
As described in the ICH-E2A guideline, a serious adverse reaction corresponds to any untoward
medical occurrence that at any dose results in death, is life-threatening, requires inpatient
hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or
incapacity, is a congenital anomaly/birth defect.
The characteristics/consequences should be considered at the time of the reaction to determine the
seriousness of a case. For example, life-threatening refers to a reaction in which the patient was at risk
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have
caused death if more severe.
Medical judgement should be exercised in deciding whether other situations should be considered as
serious reactions. Some medical events may jeopardise the patient or may require an intervention to
prevent one of the above characteristics/consequences. Such important medical events should be
considered as serious3. The EudraVigilance Expert Working Group has co-ordinated the development of
an important medical event (IME) terms list based on the Medical Dictionary for Regulatory Activities
(MedDRA). This IME list aims to facilitate the classification of suspected adverse reactions, the analysis
of aggregated data and the assessment of the Individual Case Safety Reports (ICSRs) in the
framework of the day-to-day pharmacovigilance activities. The IME list is intended for guidance
2 See VI.C.6 as regards the electronic reporting of ICSRs in the EU.
3 Examples are provided in Section II.B of ICH E2A guideline.
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purposes only and is available on the EudraVigilance web site4 to stakeholders who wish to use it for
their pharmacovigilance activities. It is regularly updated in line with the latest version of MedDRA.
VI.A.2.5. Individual Case Safety Report (ICSR)
This refers to the format and content for the reporting of one or several suspected adverse reactions in
relation to a medicinal product that occur in a single patient at a specific point of time. A valid ICSR
should include at least one identifiable reporter, one single identifiable patient, at least one suspect
adverse reaction and at least one suspect medicinal product.
4 (http://eudravigilance.ema.europa.eu/human/textforIME.asp).
http://eudravigilance.ema.europa.eu/human/textforIME.asp
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VI.B. Structures and Processes
Section B of this Module highlights the general principles in relation to the collection, recording and
reporting of reports of suspected adverse reactions associated with medicinal products for human use,
which are applicable to competent authorities and marketing authorisation holders. The definitions and
recommendations provided in VI.A should be followed. EU requirements are presented in VI.C.
VI.B.1. Collection of reports
Competent authorities and marketing authorisation holders should take appropriate measures in order
to collect and collate all reports of suspected adverse reactions associated with medicinal products for
human use originating from unsolicited or solicited sources.
For this purpose, a pharmacovigilance system should be developed to allow the acquisition of sufficient
information for the scientific evaluation of those reports.
The system should be designed so that it helps to ensure that the collected reports are authentic,
legible, accurate, consistent, verifiable and as complete as possible for their clinical assessment.
All notifications that contain pharmacovigilance data should be recorded and archived in compliance
with the applicable data protection requirements (see VI.C.6.2.2.8 for EU recommendations).
The system should also be structured in a way that allows for reports of suspected adverse reactions to
be validated (see VI.B.2) in a timely manner and exchanged between competent authorities and
marketing authorisation holders within the legal reporting time frame (see VI.B.7.1).
In accordance with the ICH-E2D guideline, two types of safety reports are distinguished in the post-
authorisation phase; reports originating from unsolicited sources and those reported as solicited.
VI.B.1.1. Unsolicited reports
VI.B.1.1.1. Spontaneous reports
A spontaneous report is an unsolicited communication by a healthcare professional, or consumer to a
competent authority, marketing authorisation holder or other organisation (e.g. Regional
Pharmacovigilance Centre, Poison Control Centre) that describes one or more suspected adverse
reactions in a patient who was given one or more medicinal products and that does not derive from a
study or any organised data collection systems where adverse events reporting is actively sought, as
defined in VI.B.1.2.
Stimulated reporting that occurs consequent to a “Direct Healthcare Professional Communication”,
publication in the press, questioning of healthcare professionals by company representatives,
communication from patients’ organisations to their members, or class action lawsuits should be
considered spontaneous reports.
Unsolicited consumer adverse reactions reports should be handled as spontaneous reports irrespective
of any subsequent “medical confirmation”.
The reporting modalities and applicable time frames for spontaneous reports are described in VI.B.7
and VI.B.8.
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VI.B.1.1.2. Literature reports
The scientific and medical literature is a significant source of information for the monitoring of the
safety profile and of the risk-benefit balance of medicinal products, particularly in relation to the
detection of new safety signals or emerging safety issues. Marketing authorisation holders are
therefore expected to maintain awareness of possible publications through a systematic literature
review of widely used reference databases (e.g. Medline, Excerpta Medica or Embase) no less
frequently than once a week. The marketing authorisation holder should ensure that the literature
review includes the use of reference databases that contain the largest reference of articles in relation
to the medicinal product properties5. In addition, marketing authorisation holders should have
procedures in place to monitor scientific and medical publications in local journals in countries where
medicinal products have a marketing authorisation, and to bring them to the attention of the company
safety department as appropriate.
Reports of suspected adverse reactions from the scientific and medical literature, including relevant
published abstracts from meetings and draft manuscripts, should be reviewed and assessed by
marketing authorisation holders to identify and record ICSRs originating from spontaneous reports or
non-interventional post-authorisation studies.
If multiple medicinal products are mentioned in the publication, only those which are identified by the
publication's author(s) as having at least a possible causal relationship with the suspected adverse
reaction should be considered by the concerned marketing authorisation holder(s).
Valid ICSRs should be reported according to the modalities detailed in VI.B.7 and VI.B.8.
One case should be created for each single patient identifiable based on characteristics provided in
VI.B.2. Relevant medical information should be provided and the publication author(s) should be
considered as the primary source(s).
EU specific requirements, as regards medicinal products and scientific and medical publications, which
are not monitored by the Agency and for which valid ISCRs shall be reported by marketing
authorisation holders, are provided in VI.C.2.2.3.
VI.B.1.1.3. Reports from other sources
If a marketing authorisation holder becomes aware of a report of suspected adverse reactions
originating from a non-medical source, for example the lay press or other media, it should be handled
as a spontaneous report. Every attempt should be made to follow-up the case to obtain the minimum
information that constitutes a valid ICSR. The same reporting time frames should be applied as for
other spontaneous reports.
VI.B.1.1.4. Information on suspected adverse reactions from the internet or digital media
Marketing authorisation holders should regularly screen internet or digital media6 under their
management or responsibility, for potential reports of suspected adverse reactions. In this aspect,
digital media is considered to be company sponsored if it is owned, paid for and/or controlled by the
marketing authorisation holder7. The frequency of the screening should allow for potential valid ICSRs
to be reported to the competent authorities within the appropriate reporting timeframe based on the
5 See VI. Appendix 2. for the detailed guidance on the monitoring of medical and scientific literature.
6 Although not exhaustive, the following list should be considered as digital media: web site, web page, blog, vlog, social
network, internet forum, chat room, health portal.
7 A donation (financial or otherwise) to an organisation/site by a marketing authorisation holder does not constitute
ownership, provided that the marketing authorisation holder does not control the final content of the site.
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date the information was posted on the internet site/digital medium. Marketing authorisation holders
may also consider utilising their websites to facilitate the collection of reports of suspected adverse
reactions (See VI.C.2.2.1).
If a marketing authorisation holder becomes aware of a report of suspected adverse reaction described
in any non-company sponsored digital medium, the report should be assessed to determine whether it
qualifies for reporting.
Unsolicited cases of suspected adverse reactions from the internet or digital media should be handled
as spontaneous reports. The same reporting time frames as for spontaneous reports should be applied
(see VI.B.7).
In relation to cases from the internet or digital media, the identifiability of the reporter refers to the
existence of a real person, that is, it is possible to verify the contact details of the reporter (e.g., an
email address under a valid format has been provided). If the country of the primary source is missing,
the country where the information was received, or where the review took place, should be used as the
primary source country.
VI.B.1.2. Solicited reports
As defined in ICH-E2D guideline, solicited reports of suspected adverse reactions are those derived
from organised data collection systems, which include clinical trials, non-interventional studies,
registries, post-approval named patient use programmes, other patient support and disease
management programmes, surveys of patients or healthcare providers, compassionate use or name
patient use, or information gathering on efficacy or patient compliance. Adverse reactions reports
obtained from any of these data collection systems should not be considered spontaneous. This is with
the exception of suspected adverse reactions originating from certain compassionate use or named
patient use where adverse events are not actively sought (See VI.C.1.2.2).
For the purpose of safety reporting, solicited reports should be classified as study reports, and should
have an appropriate causality assessment, to consider whether they refer to suspected adverse
reactions and therefore meet the criteria for reporting.
General reporting rules for suspected adverse reactions occurring in organised data collection systems
conducted in the EU under the scope of Directive 2001/83/EC, Regulation (EC) No 726/2004 or
Directive 2001/20/EC, are presented in VI.C.1.
VI.B.2. Validation of reports
Only valid ICSRs qualify for reporting. All reports of suspected adverse reactions should therefore be
validated before reporting them to the competent authorities to make sure that the minimum criteria
for reporting are included in the reports (ICH-E2D guideline). This is:
• One or more identifiable reporter (primary source), characterised by qualification (e.g. physician,
pharmacist, other healthcare professional, lawyer, consumer or other non-healthcare professional)
name, initials or address8. Whenever possible, contact details for the reporter should be recorded
so that follow-up activities can be performed. However, if the reporter does not wish to provide
contact details, the ICSR should still be considered as valid providing the organisation who was
informed of the case was able to confirm it directly with the reporter. All parties providing case
information or approached for case information should be identifiable, not only the initial reporter.
8 Local data privacy laws regarding patient’s and reporter’s identifiability might apply.
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• One single identifiable patient characterised by initials, patient identification number, date of birth,
age, age group or gender. The information should be as complete as possible9.
• One or more suspected substance/medicinal product (see VI.A.2.2).
• One or more suspected adverse reaction (see VI.A.2.1). If the primary source has made an explicit
statement that a causal relationship between the medicinal product and the adverse event has
been excluded and the receiver (competent authority or marketing authorisation holder) agrees
with this, the report does not qualify as a valid ICSR since the minimum information is
incomplete10. The report does not also qualify as a valid ICSR if it is reported that the patient
experienced an unspecified adverse reaction and there is no information provided on the type of
adverse reaction experienced. Similarly, the report is not valid if only an outcome (or consequence)
is notified and (i) no further information about the clinical circumstances is provided to consider it
as a suspected adverse reaction, or (ii) the primary source has not indicated a possible causal
relationship with the suspected medicinal product. For instance a marketing authorisation holder is
made aware that a patient was hospitalised or died, without any further information. In this
particular situation, medical judgement should always be applied in deciding whether the notified
information is an adverse reaction or an event. For example, a report of sudden death would
usually need to be considered as a case of suspected adverse reaction and reported.
The lack of any of these four elements means that the case is considered incomplete and does not
qualify for reporting. Competent authorities and marketing authorisation holders are expected to
exercise due diligence in following up the case to collect the missing data elements. Reports, for which
the minimum information is incomplete, should nevertheless be recorded within the pharmacovigilance
system for use in on-going safety evaluation activities. Recommendations on the electronic reporting of
valid ICSRs, when missing information has been obtained, are provided in VI.C.6.2.3.8.
When collecting reports of suspected adverse reactions via the internet or digital media, the term
“identifiable” refers to the possibility of verification of the existence of a reporter and a patient (see
VI.B.1.1.4).
When one party (competent authority or a marketing authorisation holder) is made aware that the
primary source may also have reported the suspected adverse reaction to another concerned party,
the report should still be considered as a valid ICSR. All the relevant information necessary for the
detection of the duplicate case should be included in the ICSR11.
A valid case of suspected adverse reaction initially submitted by a consumer cannot be downgraded to
a report of non-related adverse event if the contacted healthcare professional (nominated by the
consumer for follow-up information) disagrees with the consumer’s suspicion (see VI.A.2.1.1). In this
situation, the opinions of both the consumer and the healthcare professional should be included in the
ICSR. Guidance on the reporting of the medical confirmation of a case, provided in ICH-E2B(R2)
guideline Section A.1.14 (“Was the case medically confirmed, if not initially from a healthcare
professional?”), should be followed.
For solicited reports of suspected adverse reactions (see VI.B.1.2), where the receiver disagrees with
the reasonable possibility of causal relationship between the suspected medicinal product and the
adverse reaction expressed by the primary source, the case should not be downgraded to a report of
non-related adverse event. The opinions of both, the primary source and the receiver, should be
recorded in the ICSR.
9 See Footnote 8.
10 There is no suspected adverse reaction.
11 For further guidance on reporting of other duplicate ICSRs, refer to Section A.1.11 “Other case identifiers in previous
transmission” of ICH-E2B(R2) guideline.
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The same principle applies to the ICSR seriousness criterion, which should not be downgraded from
serious to non-serious if the receiver disagrees with the seriousness reported by the primary source.
VI.B.3. Follow-up of reports
When first received, the information in suspected adverse reactions reports may be incomplete. These
reports should be followed-up as necessary to obtain supplementary detailed information significant for
the scientific evaluation of the cases. This is particularly relevant for monitored events of special
interest, prospective reports of pregnancy, cases notifying the death of a patient, cases reporting new
risks or changes in the known risks. This is in addition to any effort to collect missing minimum
information (see VI.B.2). Any attempt to obtain follow-up information should be documented.
Follow-up methods should be tailored towards optimising the collection of missing information. This
should be done in ways that encourage the primary source to submit new information relevant for the
scientific evaluation of a particular safety concern. The use of targeted specific forms in the local
language should avoid requesting the primary source to repeat information already provided in the
initial report and/or to complete extensive questionnaires, which could discourage future spontaneous
reporting. Therefore, consideration should be given to pre-populating some data fields in those follow-
up report forms to make their completion by the primary source easy.
When information is received directly from a consumer suggesting that an adverse reaction may have
occurred, if the information is incomplete, attempts should be made to obtain consent to contact a
nominated healthcare professional to obtain further follow-up information. When such a case, initially
reported by a consumer, has been confirmed (totally or partially) by a healthcare professional, this
information should be clearly highlighted in the ICSR12.
For suspected adverse reactions relating to biological medicinal products, the definite identification of
the concerned product with regard to its manufacturing is of particular importance. Therefore, all
appropriate measures should be taken to clearly identify the name of the product and the batch
number. A business process map in relation to the mandatory follow-up of information for the
identification of suspected biological medicinal products is presented in VI.Appendix 1..
For cases related to vaccines, the recommendations provided in the Guideline on the conduct of
Pharmacovigilance for Vaccines for Pre-and Post-exposure Prophylaxis against Infectious Diseases13
should also be followed as appropriate.
VI.B.4. Data management
Electronic data and paper reports of suspected adverse reactions should be stored and treated in the
same way as other medical records with appropriate respect for confidentiality regarding patients’ and
reporters’ identifiability and in accordance with local data privacy laws. Confidentiality of patients'
records including personal identifiers, if provided, should always be maintained. Identifiable personal
details of reporting healthcare professionals should be kept in confidence. With regards to patient’s and
reporter’s identifiability, case report information should be transmitted between stakeholders
(marketing authorisation holders or competent authorities) in accordance with local data privacy laws
(see VI.C.6.2.2.8 for the processing of personal data in ICSRs in the EU).
In order to ensure pharmacovigilance data security and confidentiality, strict access controls should be
applied to documents and to databases to authorised personnel only. This security extends to the
12 For further guidance on reporting this information, refer to ICH-E2B(R2) guideline, Section A.1.14 (“Was the case
medically confirmed, if not initially from a healthcare professional?”).
13 (Ref.: EMEA/CHMP/PhVWP/503449/2007)
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/11/WC500011272.pdf
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complete data path. In this aspect, procedures should be implemented to ensure security and non-
corruption of data during data transfer.
When transfer of pharmacovigilance data occurs within an organisation or between organisations
having concluded contractual agreements, the mechanism should be such that there is confidence that
all notifications are received; in that, a confirmation and/or reconciliation process should be
undertaken.
Correct data entry, including the appropriate use of terminologies, should be verified by quality
assurance auditing, either systematically or by regular random evaluation. Data entry staff should be
instructed in the use of the terminologies, and their proficiency confirmed.
Data received from the primary source should be treated in an unbiased and unfiltered way and
inferences as well as imputations should be avoided during data entry or electronic transmission. The
reports should include the verbatim text as used by the primary source or an accurate translation of it.
The original verbatim text should be coded using the appropriate terminology as described in VI.B.8. In
order to ensure consistency in the coding practices, it is recommended to use, where applicable, the
translation of the terminology in the local language to code the verbatim text.
Electronic data storage should allow traceability (audit trail) of all data entered or modified, including
dates and sources of received data, as well as dates and destinations of transmitted data.
A procedure should be in place to account for identification and management of duplicate cases at data
entry and during the generation of aggregated reports (see VI.C.6.2.4).
VI.B.5. Quality management
Competent authorities and marketing authorisation holders should have a quality management system
in place to ensure compliance with the necessary quality standards at every stage of case
documentation, such as data collection, data transfer, data management, data coding, case validation,
case evaluation, case follow-up, ICSR reporting and case archiving (see VI.C.6.2.4 and Module I).
Conformity of stored data with initial and follow-up reports should be verified by quality control
procedures, which permit for the validation against the original data or images thereof. In this aspect,
the source data (e.g., letters, emails, records of telephone calls that include details of an event) or an
image of the source data should be easily accessible.
Clear written standard operating procedures should guarantee that the roles and responsibilities and
the required tasks are clear to all parties involved and that there is provision for proper control and,
when needed, change of the system. This is equally applicable to activities that are contracted out to
third parties, whose procedures should be reviewed to verify that they are adequate and compliant
with applicable requirements.
Staff directly performing pharmacovigilance activities, should be appropriately trained in applicable
pharmacovigilance legislation and guidelines in addition to specific training in report processing
activities for which they are responsible and/or undertake. Other personnel who may receive or
process safety reports (e.g. clinical development, sales, medical information, legal, quality control)
should be trained in adverse event collection and reporting in accordance with internal policies and
procedures.
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VI.B.6. Special situations
VI.B.6.1. Use of a medicinal product during pregnancy or breastfeeding
a. Pregnancy
Reports, where the embryo or foetus may have been exposed to medicinal products (either through
maternal exposure or transmission of a medicinal product via semen following paternal exposure),
should be followed-up in order to collect information on the outcome of the pregnancy and
development of the child after birth. The recommendations provided in the Guideline on the Exposure
to Medicinal Products during Pregnancy: Need for Post-Authorisation Data14 should be considered as
regard the monitoring, collection and reporting of information in these specific situations in order to
facilitate the scientific evaluation. When an active substance (or one of its metabolites) has a long half-
life, this should be taken into account when assessing the possibility of exposure of the embryo, if the
medicinal product was taken before conception.
Not infrequently, pregnant women or healthcare professionals will contact either competent authorities
or marketing authorisation holders to request information on the teratogenicity of a medicinal product
and/or experience of use during pregnancy. Reasonable attempts should be made to obtain
information on any possible medicinal product exposure to an embryo or foetus and to follow-up on the
outcome of the pregnancy.
Reports of exposure to medicinal products during pregnancy should contain as many detailed elements
as possible in order to assess the causal relationships between any reported adverse events and the
exposure to the suspected medicinal product. In this context the use of standard structured
questionnaires is recommended.
Individual cases with an abnormal outcome associated with a medicinal product following exposure
during pregnancy are classified as serious reports and should be reported, in accordance with the
requirements outlined in VI.B.715.
This especially refers to:
• reports of congenital anomalies or developmental delay, in the foetus or the child;
• reports of foetal death and spontaneous abortion; and
• reports of suspected adverse reactions in the neonate that are classified as serious.
Other cases, such as reports of induced termination of pregnancy without information on congenital
malformation, reports of pregnancy exposure without outcome data or reports which have a normal
outcome, should not be reported since there is no suspected adverse reaction. These reports should
however be collected and discussed in the periodic safety update reports (See Module VII).
However, in certain circumstances, reports of pregnancy exposure with no suspected reactions may
necessitate to be reported. This may be a condition of the marketing authorisation or stipulated in the
risk management plan; for example pregnancy exposure to medicinal products contraindicated in
pregnancy or medicinal products with a special need for surveillance because of a high teratogenic
potential (e.g. thalidomide, isotretinoin).
14 (Ref.: EMEA/CHMP/313666/2005)
15 See VI.C.6.2.3.1 for electronic reporting recommendations in the EU.
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/11/WC500011303.pdf
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A signal of a possible teratogen effect (e.g. through a cluster of similar abnormal outcomes) should be
notified immediately to the competent authorities in accordance with the recommendations presented
in VI.C.2.2.6.
b. Breastfeeding
Suspected adverse reactions which occur in infants following exposure to a medicinal product from
breast milk should be reported in accordance with the criteria outlined in VI.B.716.
VI.B.6.2. Use of a medicinal product in a paediatric or elderly population
The collection of safety information in the paediatric or elderly population is important. Reasonable
attempts should therefore be made to obtain and submit the age or age group of the patient when a
case is reported by a healthcare professional, or consumer in order to be able to identify potential
safety signals specific to a particular population.
As regards the paediatric population, the guidance published by the Agency17 on the conduct of
pharmacovigilance in this population should be followed.
VI.B.6.3. Reports of overdose, abuse, off-label use, misuse, medication
error or occupational exposure
For the purpose of this Module, medication error refers to any unintentional error in the prescribing,
dispensing, or administration of a medicinal product while in the control of the healthcare professional,
patient or consumer.
Reports of overdose, abuse, off-label use, misuse, medication error or occupational exposure with no
associated adverse reaction should not be reported as ICSRs. They should be considered in periodic
safety update reports as applicable. When those reports constitute safety issues impacting on the risk-
benefit balance of the medicinal product, they should be notified to the competent authorities in
accordance with the recommendations provided in VI.C.2.2.6.
Reports associated with suspected adverse reactions should be subject to reporting in accordance with
the criteria outlined in VI.B.7 and with the electronic reporting requirements described in VI.C.6.2.3.3.
They should be routinely followed-up to ensure that the information is as complete as possible with
regards to the symptoms, treatments, outcomes, context of occurrence (e.g., error in prescription,
administration, dispensing, dosage, unauthorised indication or population, etc.).
VI.B.6.4. Lack of therapeutic efficacy
Reports of lack of therapeutic efficacy should be recorded and followed-up if incomplete. They should
not normally be reported, but should be discussed in periodic safety update reports as applicable.
However, in certain circumstances, reports of lack of therapeutic efficacy may require to be reported
within a 15-day time frame (See VI.C.6.2.3.4 as regards electronic reporting in the EU). Medicinal
products used in critical conditions or for the treatment of life-threatening diseases, vaccines,
contraceptives are examples of such cases. This applies unless the reporter has specifically stated that
the outcome was due to disease progression and was not related to the medicinal product.
Clinical judgement should be used when considering if other cases of lack of therapeutic efficacy
qualify for reporting. For example, an antibiotic used in a life-threatening situation where the medicinal
16 See Footnote 15.
17 Guideline on conduct of pharmacovigilance for medicines used by the paediatric population
(EMEA/CHMP/PhVWP/235910/2005- rev.1).
http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003764.pdf
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product was not in fact appropriate for the infective agent should not be reported. However, a life-
threatening infection, where the lack of therapeutic efficacy appears to be due to the development of a
newly resistant strain of a bacterium previously regarded as susceptible, should be reported within 15
days.
For vaccines, cases of lack of therapeutic efficacy should be reported, in particular with the view to
highlight potential signals of reduced immunogenicity in a sub-group of vaccinees, waning immunity,
or strain replacement. With regard to the latter, it is considered that spontaneously reported cases of
lack of therapeutic efficacy by a healthcare professional may constitute a signal of strain replacement.
Such a signal may need prompt action and further investigation through post-authorisation safety
studies as appropriate. General guidance regarding the monitoring of vaccines failure, provided in the
Report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance18, may be followed.
VI.B.7. Reporting of ICSRs
Only valid ICSRs (see VI.B.2) should be reported. The clock for the reporting of a valid ICSR starts as
soon as the information containing the minimum reporting criteria has been brought to the attention of
the national or regional pharmacovigilance centre of a competent authority or of any personnel of the
marketing authorisation holder, including medical representatives and contractors. This date should be
considered as day zero. In practice this is the first business day the receiver becomes aware of the
information.
Where the marketing authorisation holder has set up contractual arrangements with a person or an
organisation, explicit procedures and detailed agreements should exist between the marketing
authorisation holder and the person/organisation to ensure that the marketing authorisation holder can
comply with the reporting obligations. These procedures should in particular specify the processes for
exchange of safety information, including timelines and regulatory reporting responsibilities and should
avoid duplicate reporting to the competent authorities.
For ICSRs described in the scientific and medical literature (See VI.B.1.1.2), the clock starts (day zero)
with awareness of a publication containing the minimum information for reporting. Where contractual
arrangements are made with a person/organisation to perform literature searches and/or report valid
ICSRs, detailed agreements should exist to ensure that the marketing authorisation holder can comply
with the reporting obligations.
When additional significant information is received for a previously reported case, the reporting time
clock starts again for the submission of a follow-up report from the date of receipt of the relevant
follow-up information. For the purpose of reporting, significant follow-up information corresponds to
new medical or administrative information that could impact on the assessment or management of a
case or could change its seriousness criteria; non-significant information includes updated comments
on the case assessment or corrections of typographical errors in the previous case version. See also
VI.C.6.2.2.7 as regards the distinction between significant and non-significant follow-up information.
VI.B.7.1. Reporting time frames
In general, the reporting of serious valid ICSRs is required as soon as possible, but in no case later
than 15 calendar days after initial receipt of the information by the national or regional
pharmacovigilance centre of a competent authority or by any personnel of the marketing authorisation
holder, including medical representatives and contractors. This applies to initial and follow-up
information. Where a case initially reported as serious becomes non-serious, based on new follow-up
18 Definition and Application of Terms for vaccine Pharmacovigilance, 2012
http://whqlibdoc.who.int/publications/2012/9789290360834_eng.pdf
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information, this information should still be reported within 15 days; the reporting time frame for non-
serious reports should then be applied for the subsequent follow-up reports.
Information as regards the reporting time frame of non-serious valid ICSRs in the EU is provided in
VI.C.3.
VI.B.8. Reporting modalities
Taking into account the international dimension of adverse reactions reporting and the need to achieve
harmonisation and high quality between all involved parties, ICSRs should be submitted electronically
as structured data with the use of controlled vocabularies for the relevant data elements where
applicable. In this aspect, with regard to the content and format of electronic ICSRs, competent
authorities and marketing authorisation holders should adhere to the following internationally agreed
ICH19 guidelines and standards:
• ICH M1 terminology - Medical Dictionary for Regulatory Activities (MedDRA);
• MedDRA Term Selection: Points to Consider Document - The latest version of the ICH-endorsed
Guide for MedDRA Users;
• ICH M2 EWG - Electronic Transmission of Individual Case Safety Reports Message Specification;
• ICH E2B(R2) - Maintenance of the ICH Guideline on Clinical Safety Data Management: Data
Elements for Transmission of Individual Case Safety Reports;
• ICH E2B Implementation Working Group - Questions & Answers (R5) (March 3, 2005);
As technical standards evolve over time, the above referred documents may require revision and
maintenance. In this context, the latest version of these documents should always be taken into
account.
Information regarding EU specific reporting modalities is provided in VI.C.4.
19 http://www.ich.org/
http://www.ich.org/
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VI.C. Operation of the EU Network
Section C of this Module highlights the EU specific requirements, as defined in Directive 2001/83/EC
and Regulation (EC) No 726/2004, in relation to the collection, management and reporting of reports
of suspected adverse reactions (serious and non-serious) associated with medicinal products for
human use authorised in the EU, independently of their condition of use. They are applicable to
competent authorities in Member States and/or to marketing authorisation holders. Section C should
be read in conjunction with the definitions and general principles detailed in VI.A and VI.B of this
Module and with the requirements provided in Chapter IV, V and IX of the Commission Implementing
Regulation (EU) No 520/2012 [IR].
VI.C.1. Interface with safety reporting rules for clinical trials and post
authorisation studies in the EU
The pharmacovigilance rules laid down in Directive 2001/83/EC and Regulation (EC) No 726/2004 do
not apply to investigational medicinal products and non-investigational medicinal products20 used in
clinical trials conducted in accordance with Directive 2001/20/EC21.
Post-authorisation safety or efficacy studies requested by competent authorities in Member States in
accordance with Directive 2001/83/EC or Regulation (EC) No 726/2004, or conducted voluntarily by
marketing authorisation holders, can either be clinical trials or non-interventional studies as shown in
Figure VI.1. The safety reporting falls therefore either under the scope of Directive 2001/20/EC for any
clinical trials or under the provisions set out in Directive 2001/83/EC and Regulation (EC) No 726/2004
for any non-interventional studies. Suspected adverse reactions should not be reported under both
regimes, that is Directive 2001/20/EC as well as Regulation (EC) No 726/2004 and Directive
2001/83/EC as this creates duplicate reports.
Further guidance on post-authorisation safety studies is provided in Module VIII.
The different types of studies and clinical trials which can be conducted in the EU are illustrated in
Figure VI.1. The safety reporting for clinical trials corresponding to Section A, B, C and D of Figure VI.1
follows the requirements of Directive 2001/20/EC. The safety reporting for non-interventional studies
corresponding to section E and F follows the requirements of Directive 2001/83/EC and Regulation
(EC) No 726/2004. The reporting rules of solicited reports of suspected adverse reactions to the
EudraVigilance database modules are dependent on the types of organised collection systems where
they occurred; recommendations provided in VI.C.6.2.1 should be followed.
20 For guidance on these terms, see The rules governing medicinal product in the European Union, Volume 10, Guidance
applying to clinical Trials, Guidance on Investigational Medicinal Products and Non-Investigational Medicinal Products
(NIMPs) (Ares(2011)300458 - 18/03/2011).
21 See [DIR Art 3(3), Art 107(1) third subparagraph].
http://ec.europa.eu/health/files/eudralex/vol-10/imp_03-2011.pdf
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Figure VI.1. Diagram illustrating different types of clinical trials and studies in the EU
Section A: Clinical trials, which fall under the scope of Directive 2001/20/EC and which are conducted when no
marketing authorisation exists in the EU.
Section B: Clinical trials, which fall under the scope of Directive 2001/20/EC and which are conducted in the post-
authorisation period, e.g. for new indication.
Section C: Post-authorisation clinical trials conducted in accordance with the summary of product characteristics (SmPC)
indication and condition of use, but which fall under the scope of Directive 2001/20/EC due to the nature of
the intervention.
Section D: Post-authorisation safety or efficacy clinical trials requested in accordance with Directive 2001/83/EC or
Regulation (EC) No 726/2004 or conducted voluntarily by marketing authorisation holders, but which fall
under the scope of Directive 2001/20/EC due to the nature of the intervention.
Section E: Non-interventional post-authorisation safety or efficacy studies requested in accordance with Directive
2001/83/EC or Regulation (EC) No 726/2004 or conducted voluntarily by the marketing authorisation holders
and which follow the same legal requirements.
Section F: Non-interventional post-authorisation studies conducted in accordance with SmPC indication and condition of
use and which fall under the scope of Directive 2001/83/EC or Regulation (EC) No 726/2004.
VI.C.1.1. Interface with clinical trials
A suspected adverse reaction to an investigational medicinal product occurring in a clinical trial which
falls under the scope of Directive 2001/20/EC is only to be addressed by the sponsor based on the
requirements detailed in that Directive. It is therefore excluded from the scope of this Module even if
the clinical trial where the suspected adverse reaction occurred is a post-authorisation safety or
efficacy study, requested in accordance with Directive 2001/83/EC or Regulation (EC) No 726/2004, or
conducted voluntarily.
If a clinical trial, conducted under the scope of Directive 2001/20/EC, yields safety concerns which
impact on the risk-benefit balance of an authorised medicinal product, the competent authorities in the
Member States where the medicinal product is authorised and the Agency should be notified
immediately in accordance with the modalities detailed in VI.C.2.2.6. This applies as well if a safety
concern arises from a clinical trial conducted exclusively outside the EU.
The safety data from clinical trials to be presented in the relevant sections of the periodic safety
update report of the authorised medicinal product are detailed in Module VII.
Non-interventional
studies
Clinical trials
A B
Pre-authorisation Post-authorisation
C
F
D
Safety &
Efficacy
E
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Where an untoward and unintended response originating from a clinical trial conducted in accordance
with Directive 2001/20/EC, is suspected to be related only to a non-investigational medicinal product
(or another medicinal product, which is not part of the clinical trial protocol) and does not result from a
possible interaction with the investigational medicinal product, it does not follow the expedited
reporting requirements of Directive 2001/20/EC, which apply only to the investigational medicinal
product. The investigator or the sponsor is encouraged to report the case to the competent authority in
the Member State where the reaction occurred or to the marketing authorisation holder of the
suspected medicinal product, but not to both to avoid duplicate reporting22. Where made aware of such
case, the competent authority or the marketing authorisation holder should apply the reporting
requirements described in VI.C.3, VI.C.4 and VI.C.6. As regards electronic reporting, the
recommendations detailed in VI.C.6.2.3.7 should be followed.
VI.C.1.2. Interface with post-authorisation studies
In the context of this module, post-authorisation studies are organised data collection systems which
do not fall under the scope of the clinical trials Directive 2001/20/EC.
They include non-interventional post-authorisation studies, compassionate use, named patient use,
other patient support and disease management programmes, registries, surveys of patients or
healthcare providers, and information gathering on efficacy or patient compliance. They may involve
the receipt of information on adverse events.
Competent authorities in Member States and marketing authorisation holders should have in place a
system to collect full and comprehensive case information and to evaluate that information in order to
determine whether the collected adverse events are possibly related to the studied (or supplied)
medicinal product and should be classified and processed as ICSRs of suspected adverse reactions.
Different methods may be applied for assessing the causal role of a medicinal product on the reported
adverse event (e.g. WHO-UMC system for standardised case causality assessment). In this situation,
the levels of causality, which correspond to a reasonable possibility of causal relationship, should be
established in advance in order to determine when an adverse event is considered as an adverse
reaction.
Only valid ICSRs (See VI.B.2) of adverse reactions, which are suspected to be related to the studied
(or supplied) medicinal product by the primary source or the receiver of the case, should be reported.
They should be considered as solicited reports (with the exception of certain reports from
compassionate use or named patient use (See VI.C.1.2.2)) and reported by marketing authorisation
holders or competent authorities in Member States in accordance with the requirements provided in
VI.C.3, VI.C.4 and VI.C.6. Other reports of adverse events should only be included in the study report,
where applicable.
Electronic reporting recommendations for cases originating in post-authorisation studies are detailed in
VI.C.6.2.3.7.
It may happen that reports of adverse reactions are only suspected to be related to other medicinal
products which are not subject to the scope of the post-authorisation study. If there is no interaction
with the studied (or supplied) medicinal product, these reports should be notified by the primary
source, to the competent authority in the Member State where the reaction occurred or to the
marketing authorisation holder of the suspected medicinal product, but not to both to avoid duplicate
22 See The rules governing medicinal product in the European Union, Volume 10, Detailed guidance on the collection,
verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human
use (‘CT-3’), (2011/C 172/01).
http://who-umc.org/Graphics/24734.pdf
http://ec.europa.eu/health/files/eudralex/vol-10/2011_c172_01/2011_c172_01_en.pdf
http://ec.europa.eu/health/files/eudralex/vol-10/2011_c172_01/2011_c172_01_en.pdf
http://ec.europa.eu/health/files/eudralex/vol-10/2011_c172_01/2011_c172_01_en.pdf
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reporting. Where made aware of such case, the concerned competent authorities or marketing
authorisation holders should apply the reporting requirements described in VI.C.3 and VI.C.4 while
respecting the electronic reporting recommendations detailed in VI.C.6.2.3.7.
Further guidance on post-authorisation studies conducted by marketing authorisation holders is
provided in VI.C.2.2.2.
Academic sponsors should follow local requirements as regards the reporting of cases of suspected
adverse reactions to the competent authority in the Member State where the reaction occurred.
However, where a study is directly financed, or where the design is influenced by a marketing
authorisation holder, the marketing authorisation holder should fulfil the reporting requirements
detailed in this Module.
VI.C.1.2.1. Non-interventional studies
Non-interventional studies should be distinguished between those with primary data collection directly
from consumers and healthcare professionals, and study designs which are based on secondary use of
data such as studies based on medical chart reviews or electronic healthcare records, systematic
reviews or meta-analyses.
• Non-interventional studies with primary data collection directly from patients and healthcare
professionals should be considered as organised data collection systems where adverse events are
actively sought. Only reports of adverse reactions suspected to be related to the studied medicinal
product should be reported. Reports of adverse events should only be summarised in the study
report, where applicable.
• For non-interventional study designs which are based on secondary use of data, adverse reactions
reporting is not required. Reports of adverse events/reactions should only be summarised in the
study report, where applicable.
• In case of doubt, the reporting requirement should be clarified with the concerned competent
authorities in Member States.
• With regard the reporting of cases of suspected adverse reactions to local ethics committees and
investigators, the national legislation should be followed as applicable.
VI.C.1.2.2. Compassionate use, named patient use
Where an organisation23 or a healthcare professional, supplying a medicinal product under
compassionate use or named patient use (see VI.A.2.2 for definitions), is notified or becomes aware of
an adverse event, it should be managed as followed depending on the requirements in the concerned
Member State:
• For compassionate and named patient uses where adverse events are actively sought, only reports
of adverse reactions suspected to be related to the supplied medicinal product should be reported.
They should be considered as solicited reports.
• For compassionate and named patient uses where the reporting of adverse events is not solicited,
any notified noxious or unintended response to the supplied medicinal product should be
considered as a spontaneous report of suspected adverse reaction by the receiver of the case.
23 E.g. sponsor, applicant, marketing authorisation holder, hospital or wholesaler.
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VI.C.2. Collection of reports
VI.C.2.1. Member States responsibilities
Each Member State shall have in place a system for the collection and recording of unsolicited and
solicited reports of suspected adverse reactions that occur in its territory and which are brought to its
attention by healthcare professionals, consumers, or marketing authorisation holders24 [DIR Art 101(1)
and 107a(1)]. In this context, competent authorities in Member States shall establish procedures for
collecting and recording all reports of suspected adverse reactions that occur in their territory [IR Art
15 (2)]. The general principles detailed in VI.B, together with the reporting modalities presented in
VI.C.3, VI.C.4 and VI.C.6 should be applied to those reports. Pharmacovigilance data and documents
relating to individual authorised medicinal products shall be retained as long as the product is
authorised and for at least 10 years after the marketing authorisation has expired. However, the
documents shall be retained for a longer period where Union law or national law so requires [IR Art 16
(2)].
Each Member State shall take all appropriate measures to encourage healthcare professionals and
consumers in their territory to report suspected adverse reactions to their competent authority. In
addition, the competent authority in a Member State may impose specific obligations on healthcare
professionals. To this end, competent authorities in Member States shall facilitate in their territory the
reporting of suspected adverse reactions by means of alternative straightforward reporting systems,
accessible to healthcare professionals and consumers, in addition to web-based formats [DIR Art 102].
Information on the different ways of reporting suspected adverse reactions related to medicinal
products, shall be made publicly available including by means of national medicines web-based portals
[DIR 106(e)]. To increase awareness of the reporting systems, organisations representing consumers
and healthcare professionals may be involved as appropriate [DIR Art 102].
Standard web-based structured forms for the reporting of suspected adverse reactions by healthcare
professionals and consumers shall be developed by the Agency in collaboration with Member States in
order to collect across the EU harmonised information relevant for the evaluation of suspected adverse
reactions, including errors associated with the use of medicinal products [REG Art 25]. In this context,
core data fields for reporting will be made available by the Agency to the competent authorities in
Member States for use in their national reporting systems as applicable.
The reports of suspected adverse reactions received from healthcare professionals and consumers
should be acknowledged where appropriate and further information should be provided to the reporters
as requested and when available.
For reports submitted by a marketing authorisation holder, Member States on whose territory the
suspected adverse reaction occurred may involve the marketing authorisation holder in the follow-up
of the reports [DIR Art 107a(2)].
Each Member State shall ensure that the competent authority responsible for medicinal products within
that Member State is informed of any suspected adverse reaction, brought to the attention of any
other authority, body, institution or organisation responsible for patient safety within that Member
State, and that valid ICSRs are made available to the EudraVigilance database. Therefore, where
reports of suspected adverse reactions are sent directly to other authorities, bodies, organisations
and/or institutions within a Member State, the competent authority in that Member State shall have
data exchange agreements in place so that these reports are brought to its attention and are made
available to EudraVigilance in a timely manner[DIR Art 107a(5)]. This applies as well to reports of
24 Marketing authorisation holders shall report ICSRs to the competent authorities in Member States in accordance with the
transitional provisions set out in Article 2(4) and Article 2(5) of Directive 2010/84/EU and further detailed in VI.C.4.1.
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suspected adverse reactions arising from an error associated with the use of a medicinal product.
Those error reports of suspected adverse reactions for which a competent authority in a Member
State is made aware of, including those received from the EudraVigilance database in accordance with
Article 24(4) of Regulation (EC) No 726/2004, shall also be brought to the attention of other
authorities, bodies, organisations and/or institutions responsible for patient safety within that Member
State [DIR Art 107a(5)].
Unless there are justifiable grounds resulting from pharmacovigilance activities, individual Member
States shall not impose any additional obligations on marketing authorisation holders for the reporting
of suspected adverse reactions [DIR Art 107a(6)].
VI.C.2.2. Marketing authorisation holders responsibilities
Each marketing authorisation holder shall have in place a system for the collection and recording of all
reports of suspected adverse reactions which are brought to its attention, whether reported
spontaneously by healthcare professionals or consumers or occurring in the context of a post-
authorisation study [DIR Art 104(1), Art 107(1)]. Marketing authorisation holders shall not refuse to
consider reports of suspected adverse reactions received electronically or by any other
appropriate means from patients and healthcare professionals [Art 107(2)]. All those reports shall
be accessible at a single point within the Union [Dir Art 107(1)].
Marketing authorisation holders shall establish mechanisms enabling the traceability and follow-up of
adverse reaction reports while complying with the data protection legislation [IR Art 12 (1)].
Pharmacovigilance data and documents relating to individual authorised medicinal products shall be
retained as long as the product is authorised and for at least 10 years after the marketing
authorisation has ceased to exist. However, the documents shall be retained for a longer period where
Union law or national law so requires [IR Art 12 (2)].
With regard to the collection and recording of reports of suspected adverse reactions, marketing
authorisation holders responsibilities apply to reports related to medicinal products (see VI.A.2.2) for
which ownership cannot be excluded on the basis of one the following criteria: medicinal product
name, active substance name, pharmaceutical form, batch number or route of administration.
Exclusion based on the primary source country or country of origin of the adverse reaction is possible if
the marketing authorisation holder can demonstrate that the suspected medicinal product has never
been supplied or placed on the market in that territory or that the product is not a travel medicine
(e.g., anti-malarial medicinal product).
The marketing authorisation holder shall ensure that any information on adverse reactions, suspected
to be related to at least one of the active substances of its medicinal products authorised in the EU, is
brought to its attention by any company outside the EU belonging to the same mother company (or
group of companies) 25. The same applies to the marketing authorisation holder when having
concluded a commercial agreement with a company outside the EU for one of its medicinal product
authorised in the EU. The clock for reporting (see VI.B.7) starts when a valid ICSR is first received by
one of these companies outside the EU.
In addition to the requirements presented in this chapter, the general principles detailed in Section
VI.B, together with the reporting modalities presented in VI.C.3, VI.C.4 and VI.C.6 should be applied
by marketing authorisation holders to all reports of suspected adverse reactions.
25 As outlined in the Commission communication on the Community marketing authorization procedures for medicinal
products (98/C 229/03).
http://ec.europa.eu/health/files/eudralex/vol-1/com_1998/com_1998_en.pdf
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VI.C.2.2.1. Spontaneous reports
Marketing authorisation holders shall record all reports of suspected adverse reactions originating from
within or outside the EU, which are brought to their attention spontaneously by healthcare
professionals, or consumers. This includes reports of suspected adverse reactions received
electronically or by any other appropriate means [DIR Art 107(1), Art 107(2)]. In this context,
marketing authorisation holders may consider utilising their websites to facilitate the collection of
reports of suspected adverse reactions by providing adverse reactions forms for reporting, or
appropriate contact details for direct communication (See VI.B.1.1.4).
VI.C.2.2.2. Solicited reports
In accordance with Art 107(1) of Directive 2001/83/EC, marketing authorisation holders shall record all
reports of suspected adverse reactions originating from within or outside the EU, which occur in post-
authorisation studies, initiated, managed, or financed by them26. General guidance on post-
authorisation studies is provided in VI.C.1.2. Electronic reporting recommendations for cases
originating in post-authorisation studies are detailed in VI.C.6.2.3.7.
For post authorisation studies, marketing authorisation holders should have mechanisms in place to
collect full and comprehensive case information and to evaluate that information, in order to allow
meaningful assessment of individual cases and reporting of valid ICSRs (See VI.B.2) related to the
studied (or supplied) medicinal product. Marketing authorisation holders should therefore exercise due
diligence in establishing such system, in following-up those reports (See VI.B.3) and in seeking the
view of the primary source as regard the causal role of the studied (or supplied) medicinal product on
the notified adverse event. Where this opinion is missing, the marketing authorisation holder should
exercise its own judgement based on the information available in order to decide whether the report is
a valid ICSR, which should be reported to the competent authorities. This does not apply to study
designs based on secondary use of data for which reporting of ICSRs is not required (See VI.C.1.2.1).
Safety data to be presented in the relevant sections of the periodic safety update report of the
authorised medicinal product are detailed in Module VII.
VI.C.2.2.3. Case reports published in the scientific and medical literature
General principles in relation to the monitoring for individual cases of suspected adverse reactions
described in the scientific and medical literature are provided in VI.B.1.1.2. As regards the screening of
the scientific and medical literature, the requirements provided in this Module are part of the wider
literature searches which need to be conducted for periodic safety update reports (see Module VII).
In accordance with Article 107(3) of Directive 2001/83/EC, in order to avoid the reporting of duplicate
ICSRs, marketing authorisation holders shall only report those ICSRs described in the scientific and
medical literature which is not reviewed by the Agency, for all medicinal products containing active
substances which are not included in the list monitored by the Agency pursuant to Article 27 of
Regulation (EC) No 726/2004. Until such lists of scientific and medical literature and active substance
names are published by the Agency, marketing authorisation holders should monitor all the active
substances for which they hold a marketing authorisation in the EU by accessing a widely used
systematic literature review and reference database, in line with the principles detailed in VI.B.1.1.2
and in VI. Appendix 2
26 This does not concern donation of a medicinal product for research purpose if the marketing authorisation holder has no
influence on the study.
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Articles can be excluded from the reporting of ICSRs by the marketing authorisation holder if another
company's branded medicinal product is the suspected medicinal product. In the absence of a specified
medicinal product source and/or invented name, ownership of the medicinal product should be
assumed for articles about an active substance, unless alternative reasons for exclusion detailed
hereafter apply.
• Where ownership of the medicinal product by the marketing authorisation holder can be excluded
on the basis of the criteria detailed in VI.C.2.2;
• For individual case safety reports identified in the scientific and medical literature that originate in
a country where a company holds a marketing authorisation but has never commercialised the
medicinal product;
• For literature ICSRs which are based on an analysis from a competent authority database within
the EU. The reporting requirements remain for those ICSRs which are based on the analysis from a
competent authority database outside the EU;
• For literature articles, which present data analyses from publicly available databases or, which
summarise results from post-authorisation studies (See VI.C.1.2). This type of literature article
describes adverse reactions, which occur in a group of patients with a designated medicinal
product with the aim of identifying or quantifying a safety hazard related to a medicinal product,
and aggregated data on patients are often presented in tables or line listings. The main objective
of those studies is to detect/evaluate specific risks that could affect the overall risk-benefit balance
of a medicinal product.
New and significant safety findings presented in these articles, for which reporting is not required,
should however be discussed in the relevant sections of the concerned periodic safety update report
(see Module VII) and analysed as regards their overall impact on the medicinal product risk-benefit
profile. In addition, any new safety information, which may impact on the risk-benefit profile of a
medicinal product, should be notified immediately to the competent authorities in Member States
where the medicinal product is authorised and to the Agency in accordance with the recommendations
provided in VI.C.2.2.6.
A detailed guidance on the monitoring of the scientific and medical literature has been developed in
accordance with Article 27(3) of Regulation (EC) No 726/2004; it is included in VI. Appendix 2.
The electronic reporting recommendations regarding suspected adverse reactions reports published in
the scientific and medical literature are provided in VI.C.6.2.3.2.
VI.C.2.2.4. Suspected adverse reactions related to quality defect or falsified medicinal
products
When a report of suspected adverse reactions is associated with a suspected or confirmed falsified
medicinal product or quality defect of a medicinal product, a valid ICSR should be reported. The
seriousness of the ICSR is linked to the seriousness of the reported suspected adverse reactions in
accordance with the definitions provided in VI.A.2.4. Electronic reporting recommendations provided in
VI.C.6.2.3.5 should be followed.
In addition in order to protect public health, it may become necessary to implement urgent measures
such as the recall of one or more defective batch(es) of a medicinal product from the market.
Therefore, marketing authorisation holders should have a system in place to ensure that reports of
suspected adverse reactions related to falsified medicinal products or to quality defects of a medicinal
products are investigated in a timely fashion and that confirmed quality defects are notified separately
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to the manufacturer and to competent authorities in accordance with the provisions described in Article
13 of Directive 2003/94/EC.
VI.C.2.2.5. Suspected transmission via a medicinal product of an infectious agent
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal
product should be considered as a serious adverse reaction and such cases should be reported within
15 days in accordance with the requirements outlined in VI.C.4 27. If no other criterion is applicable,
the seriousness of this ICSR should be considered as important medical event (see VI.A.2.4). This also
applies to vaccines. Electronic reporting recommendations provided in VI.C.6.2.3.6 should be followed.
In the case of medicinal products derived from human blood or human plasma, haemovigilance
procedures may also apply in accordance with Directive 2002/98/EC. Therefore the marketing
authorisation holder should have a system in place to communicate suspected transmission via a
medicinal product of an infectious agent to the manufacturer, the relevant blood establishment(s) and
national competent authorities in Member States.
Any organism, virus or infectious particle (e.g. prion protein transmitting Transmissible Spongiform
Encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent.
A transmission of an infectious agent may be suspected from clinical signs or symptoms, or laboratory
findings indicating an infection in a patient exposed to a medicinal product.
Emphasis should be on the detection of infections/infectious agents known to be potentially
transmitted via a medicinal product, but the occurrence of unknown agents should also always be
considered.
In the context of evaluating a suspected transmission of an infectious agent via a medicinal product,
care should be taken to discriminate, whenever possible, between the cause (e.g., injection/
administration) and the source (e.g., contamination) of the infection and the clinical conditions of the
patient at the time of the infection (immuno-suppressed /vaccinee).
Confirmation of contamination (including inadequate inactivation/attenuation of infectious agents as
active substances) of the concerned medicinal product increases the evidence for transmission of an
infectious agent and may therefore be suggestive of a quality defect for which the procedures detailed
in VI.C.2.2.4 should be applied.
Medicinal products should comply with the recommendations provided in the Note for Guidance on
Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and
Veterinary Products28. For advanced therapy medicinal products, Article 14(5) of Regulation (EC) No
1394/2007 and the Guideline on Safety and Efficacy Follow-up - Risk Management of Advanced
Therapy Medicinal Products29, should also be followed as appropriate.
VI.C.2.2.6. Emerging safety issues
Events may occur, which do not fall within the definition of reportable valid ICSRs, and thus are not
subject to the reporting requirements, even though they may lead to changes in the known risk-benefit
balance of a medicinal product and/or impact on public health. Examples include:
• major safety findings from a newly completed non-clinical study;
27 See VI.C.6.2.3.6 for electronic reporting recommendations.
28 Latest revision. (Ref.: EMA/410/01).
29 (Ref.: EMEA/149995/2008)
http://ec.europa.eu/health/files/eudralex/vol-1/dir_2003_94/dir_2003_94_en.pdf
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2003:033:0030:0040:EN:PDF
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2007:324:0121:0137:en:PDF
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2007:324:0121:0137:en:PDF
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2011:073:0001:0018:EN:PDF
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• major safety concerns identified in the course of a non-interventional post-authorisation study or of
a clinical trial;
• signal of a possible teratogen effect or of significant hazard to public health;
• safety issues published in the scientific and medical literature;
• safety issues arising from the signal detection activity (see Module IX) or emerging from a new
ICSR and which impact on the risk-benefit balance of the medicinal product and/or have
implications for public health;
• safety issues related to the use outside the terms of the marketing authorisation;
• safety issues due to misinformation in the product information;
• marketing authorisation withdrawal, non-renewal, revocation or suspension outside the EU for
safety-related reasons;
• urgent safety restrictions outside the EU;
• safety issues in relation to the supply of raw material;
• lack of supply of medicines.
These events/observations, which may affect the risk-benefit balance of a medicinal product, are not to
be submitted as ICSRs. They should be notified as Emerging Safety Issues in writing to the competent
authorities in Member States where the medicinal product is authorised and to the Agency via email
(P-PV-emerging-safety-issue@ema.europa.eu); this should be done immediately when becoming
aware of them. The document should indicate the points of concern and the actions proposed in
relation to the marketing application/authorisation for the concerned medicinal product. Those safety
issues should also be analysed in the relevant sections of the periodic safety update report of the
authorised medicinal product.
VI.C.2.2.7. Period between the submission of the marketing authorisation application and
the granting of the marketing authorisation
In the period between the submission of the marketing authorisation application and the granting of
the marketing authorisation, information (quality, non-clinical, clinical) that could impact on the risk-
benefit balance of the medicinal product under evaluation may become available to the applicant30. It
is the responsibility of the applicant to ensure that this information is immediately submitted in
accordance with the modalities described in VI.C.2.2.6 to the competent authorities in the Member
States where the application is under assessment (including Reference Member State and all
concerned Member States for products assessed under the mutual recognition or decentralised
procedures) and to the Agency. For applications under the centralised procedure, the information
should also be provided to the (Co-) Rapporteur.
In the situation where a medicinal product application is under evaluation in the EU while it has already
been authorised in a third country, valid ICSRs from outside the EU, originating from unsolicited
reports (see VI.B.1.1) or solicited reports (see VI.B.1.2), should be reported in accordance with the
requirements provided in VI.C.3, VI.C.4 and VI.C.6.
30 See also Chapter 1, Section 5.1.1 of Volume 2A (Notice to Applicants) of The Rules Governing Medicinal Products in the
European Union.
mailto:P-PV-emerging-safety-issue@ema.europa.eu
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VI.C.2.2.8. Period after suspension, revocation or withdrawal of marketing authorisation
The marketing authorisation holder shall continue to collect any reports of suspected adverse reactions
related to the concerned medicinal product following the suspension of a marketing authorisation. The
reporting requirements outlined in VI.C.4 remain.
Where a marketing authorisation is withdrawn or revoked, the former marketing authorisation holder is
encouraged to continue to collect spontaneous reports of suspected adverse reactions originating
within the EU to for example facilitate the review of delayed onset adverse reactions or of
retrospectively notified cases.
VI.C.2.2.9. Period during a public health emergency
A public health emergency is a public health threat duly recognised either by the World Health
Organization (WHO) or the Community in the framework of Decision No. 2119/98/EC of the European
Parliament and of the Council. In the event of a public health emergency, regular reporting
requirements may be amended. Such arrangements will be considered on a case-by-case basis and will
be appropriately notified on the Agency website.
VI.C.2.2.10. Reports from class action lawsuits
Stimulated reports arising from class action lawsuits should be managed as spontaneous reports. Valid
ICSRs should describe adverse reactions related to the concerned medicinal product. They should be
reported in accordance with the time frames and modalities described in VI.C.3, VI.C.4 and VI.C.6.
Where large batches of potential ICSRs are received, marketing authorisation holders may request, in
exceptional circumstances, for an exemption in order to submit serious cases of suspected adverse
reactions within 30 days from their date of receipt instead of 15 days. The 90 days reporting time
frame for non-serious ICSRs remains unchanged. It will be possible to apply for this exemption only
once the functionalities of the EudraVigilance database specified in Article 24(2) of Regulation (EC) No
726/2004 are established. The request should be made to the Agency Pharmacovigilance Department.
VI.C.2.2.11. Reports from patient support programmes and market research programmes
A patient support programme is an organised system where a marketing authorisation holder receives
and collects information relating to the use of its medicinal products. Examples are post-authorisation
patient support and disease management programmes, surveys of patients and healthcare providers,
information gathering on patient compliance, or compensation/re-imbursement schemes.
A market research programme refers to the systematic collection, recording and analysis by a
marketing authorisation holder of data and findings about its medicinal products, relevant for
marketing and business development.
Safety reports originating from those programmes should be considered as solicited reports. Marketing
authorisation holders should have the same mechanisms in place as for all other solicited reports (See
VI.C.2.2.2) to manage that information and report valid cases of adverse reactions, which are
suspected to be related to the concerned medicinal product.
Valid ICSRs should be reported as solicited in accordance with the electronic reporting requirements
provided in VI.C.6.2.3.7.
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:1998:268:0001:0006:EN:PDF
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VI.C.3. Reporting time frames
The general rules in relation to the reporting of initial and follow-up reports, including those for
defining the clock start are detailed in VI.B.7.
According to Articles 107(3) and 107a(4) of Directive 2001/83/EC,
• serious valid ICSRs shall be reported by competent authorities in Member States or by marketing
authorisation holders within 15 days from the date of receipt of the reports;
• non-serious valid ICSRs shall be reported by competent authorities in Member States or by
marketing authorisation holders within 90 days from the date of receipt of the reports.
This should be done in accordance with the reporting modalities detailed in VI.C.4.
VI.C.4. Reporting modalities
In addition to the recommendations provided in VI.B.8, competent authorities in Member States and
marketing authorisation holders shall use the formats, standards and terminologies for the electronic
transmission of suspected adverse reactions as referred to in Chapter IV of the Commission
Implementing Regulation (EU) No 520/2012. ICSRs shall be used for reporting to the Eudravigilance
database suspected adverse reactions to a medicinal product that occur in a single patient at a specific
point in time [IR Art 27]. Competent authorities in Member States and marketing authorisation holders
shall also ensure that all reported electronic ICSRs are well documented and as complete as possible in
accordance with the requirements provided in [IR Art 28].
The time frames for reporting serious and non-serious valid ICSRs are provided in VI.C.3. The
recommendations provided in VI.C.6 should be adhered to as regards the electronic exchange of
pharmacovigilance information between competent authorities in Member States, marketing
authorisation holders and the Agency.
ICSRs reported electronically to the EudraVigilance database will be made accessible to stakeholders
such as competent authorities, healthcare professionals, consumers, as well as marketing authorisation
holders and research organisations in accordance with Article 24(2) of Regulation (EC) No 726/2004
and the EudraVigilance access policy31. This policy defines the overall principles of the provision of
access to EudraVigilance data in line with the current legal framework, while guaranteeing personal
data protection. As detailed in the EudraVigilance access policy, a selection of ICSRs could be
downloaded by marketing authorisation holders in ICH E2B format and in accordance with the ICH M2
message specifications, to facilitate their pharmacovigilance activities.
VI.C.4.1. Interim arrangements
In accordance with the provisions set out in Article 2(4), Article 2(5) and Article 2(6) of Directive
2010/84/EU, until the Agency can ensure the functionalities of the EudraVigilance database as
specified in Article 24(2) of Regulation (EC) No 726/2004, the following reporting requirements shall
apply to valid unsolicited and solicited ICSRs reported by healthcare professionals and non-healthcare
professionals. This is independently of the condition of use of the suspected medicinal product and of
the expectedness of the adverse reaction.
31 EudraVigilance Access Policy for Medicines for Human Use (EMA/759287/2009).
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a. Serious ICSRs
• Marketing authorisation holders shall report all serious ICSRs that occur in the EU to the competent
authority of the Member State on whose territory the suspected adverse reactions occurred.
• Marketing authorisation holders shall report to the EudraVigilance database all serious ICSRs that
occur outside the EU, including those received from competent authorities. If required by Member
States, those reports shall also be submitted to the competent authorities in the Member States in
which the medicinal product is authorised.
• Competent authorities in Member States shall ensure that all serious ICSRs that occur in their
territory and that are reported to them, including those received from marketing authorisation
holders, are made available to the EudraVigilance database. Competent authorities in Member
States should also make available, to the marketing authorisation holders of the suspected
medicinal products, all serious ICSRs reported directly to them.
b. Non-Serious ICSRs
• If required by Member States, marketing authorisation holders shall report all non-serious ICSRs
that occur in the EU to the competent authority of the Member State on whose territory the
suspected adverse reactions occurred.
Overviews of the reporting requirements of serious and non-serious reports during the interim period,
applicable to marketing authorisation holders or competent authorities in Member States, are
presented in VI. Appendix 3.1, together with a detailed business process map.
Member States reporting requirements for serious non-EU ICSRs and for non-serious EU ICSRs are also
included in this Appendix.
VI.C.4.2. Final arrangements
Once the functionalities of the EudraVigilance database specified in Article 24(2) of Regulation (EC) No
726/2004 are established, the following requirements, detailed in Articles 107(3) and 107a(4) of
Directive 2001/83/EC, shall apply within 6 months of the announcement by the Agency to valid
unsolicited and solicited ICSRs reported by healthcare professionals and non-healthcare professionals.
This is independently of the condition of use of the suspected medicinal product and of the
expectedness of the adverse reaction.
a. Serious ICSRs
• Marketing authorisation holders shall submit all serious ICSRs that occur within or outside the EU,
including those received from competent authorities outside the EU, to the EudraVigilance database
only.
• Competent authorities in Member States shall submit to the EudraVigilance database all serious
ICSRs that occur in their territory and that are directly reported to them.
b. Non-Serious ICSRs
• Marketing authorisation holders shall submit all non-serious ICSRs that occur in the EU to the
EudraVigilance database only.
• Competent authorities in Member States shall submit all non-serious ICSRs that occur in their
territory to the EudraVigilance database.
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Overviews of the reporting requirements of serious and non-serious reports, applicable to marketing
authorisation holders or competent authorities in Member States once the final arrangements are
implemented, are presented in VI. Appendix 3.2, together with a detailed business process map.
In accordance with the requirement detailed in Article 24(4) of Regulation (EC) No 726/2004 for the
final arrangements, the ICSRs submitted to the EudraVigilance database by marketing authorisation
holders shall be automatically transmitted upon receipt, to the competent authority of the Member
State where the reaction occurred. A detailed business process map is included in VI. Appendix 3.3.
VI.C.5. Collaboration with the World Health Organization and the European
Monitoring Centre for Drugs and Drug Addiction
The Agency shall make available to the WHO Collaborating Centre for International Drug Monitoring all
suspected adverse reaction reports occurring in the EU [REG Art 28c(1)]. This will take place on a
weekly basis after their transmission to the EudraVigilance database by competent authorities in
Member States or marketing authorisation holders. It will replace the requirements of Member States
participating in the WHO Programme for International Drug Monitoring to directly report to WHO
suspected adverse reactions reports occurring in their territory. This will be implemented once the
functionalities of the EudraVigilance database specified in Article 24(2) of Regulation (EC) No 726/2004
are established.
A detailed business process map for the reporting of ICSRs, from the EudraVigilance database to the
WHO Collaborating Centre for International Drug Monitoring, is presented in VI. Appendix 4.
The Agency and the European Monitoring Centre for Drugs and Drug Addiction shall also exchange
information that they receive on the abuse of medicinal products including information related to illicit
drugs [REG Art 28c(2)].
VI.C.6. Electronic exchange of safety information in the EU
Part VI.C.6 highlights the requirements, as defined in Articles 24(1) and 24(3) of Regulation (EC) No
726/2004, for the establishment and maintenance of the European database and data processing
network (the EudraVigilance database) in order to collate and share pharmacovigilance information
electronically between competent authorities in Member States, marketing authorisation holders and
the Agency, in ways which ensure the quality and integrity of the data collected.
The information provided here is relevant for the electronic exchange of ICSRs in the EU between all
stakeholders and for the electronic submission of information on medicinal products to the Agency.
VI.C.6.1. Applicable guidelines, definitions, international formats,
standards and terminologies
For the classification, retrieval, presentation, risk-benefit evaluation and assessment, electronic
exchange and communication of pharmacovigilance and medicinal product information, Member
States, marketing authorisation holders and the Agency shall adhere to the legal requirements
provided in Chapter IV of the Commission Implementing Regulation (EU) No 520/2012.
In addition the following guidelines should be applied:
• Note for guidance - EudraVigilance Human - Processing of Safety Messages and Individual Case
Safety Reports (ICSRs) (EMA/H/20665/04/Final Rev. 2) (EudraVigilance Business Rules);
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• Note for Guidance on the Electronic Data Interchange (EDI) of Individual Case Safety Reports
(ICSRs) and Medicinal Products (MPRS) in Pharmacovigilance during the pre- and post-
authorisation phase in the European economic area (EEA) (EMEA/115735/2004);
• The ICH guidelines detailed in VI.B.8;
• The ICH-M5 guideline ‘Routes of Administration Controlled Vocabulary’ (CHMP/ICH/175860/2005),
which provides standard terms for routes of administration;
The latest version of these documents should always be considered.
VI.C.6.2. Electronic Reporting of Individual Case Safety Reports
The reporting of valid ICSRs electronically, by competent authorities in Member States and marketing
authorisation holders, is mandatory for all medicinal products authorised in the EU [DIR Art 107(3), Art
107a(4)]. Non-adherence to this requirement constitutes a non-compliance with EU legislation.
Responsibilities in case of communication failure (including adherence to compliance for reporting) are
detailed in Chapter IV of the Note for Guidance on the Electronic Data Interchange (EDI) of Individual
Case Safety Reports (ICSRs) and Medicinal Product Reports (MPRs) in Pharmacovigilance during the
Pre- and Post-authorisation Phase in the European Economic Area (EEA) (EMEA/115735/2004).
Technical tools (EVWEB) have been made available by the Agency to interested electronic data
interchange partners, including small and medium-sized enterprises, to facilitate compliance with the
electronic reporting requirements as defined in EU legislation. Information is available on
EudraVigilance website32.
VI.C.6.2.1. EudraVigilance Database Modules
Two modules are available in the EudraVigilance database to address the collection of reports of
suspected adverse reactions related to medicinal products for human use, in accordance with EU
legislation:
• EudraVigilance Post-Authorisation Module (EVPM), implemented based on the requirements defined
in Regulation (EC) No 726/2004 and Directive 2001/83/EC, and
• EudraVigilance Clinical Trial Module (EVCTM), implemented based on the requirements defined in
Directive 2001/20/EC.
VI.C.6.2.1.1. Adverse reaction data collected in the EudraVigilance Post-Authorisation
Module
The adverse reaction reports collected in the EudraVigilance Post-Authorisation Module (EVPM) refer to
unsolicited reports and solicited reports which do not fall under the scope of the Clinical Trials Directive
2001/20/EC (see VI.C.1). The ICSRs should be submitted with the value 'EVHUMAN' in the data
element ‘Message receiver identifier’ (ICH M2 M.1.6).
Depending on their type, these ICSRs should be classified with one of the following options, in
accordance with the EudraVigilance business rules33:
• Data element ‘Type of report’ (ICH-E2B(R2) A.1.4):
− spontaneous report;
32 http://eudravigilance.ema.europa.eu
33 Note for guidance - EudraVigilance Human - Processing of Safety Messages and Individual Case Safety Reports (ICSRs)
(EMA/H/20665/04/Final Rev. 2).
http://eudravigilance.ema.europa.eu/human/docs/Note%20for%20Guidance%20on%20EDI%20Process%20of%20ICSRs%20Final.pdf
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002730.pdf
http://eudravigilance.ema.europa.eu/human/docs/Note%20for%20Guidance%20on%20EDI%20Process%20of%20ICSRs%20Final.pdf
http://eudravigilance.ema.europa.eu/
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− other;
− not available to sender (unknown); or
− report from study.
• In addition, when the value in the data element ICH-E2B(R2) A.1.4 is ‘Report from study’, the data
element ‘Study type in which the reaction(s)/event(s) were observed’ (ICH-E2B(R2) A.2.3.3)
should be populated with:
− individual patient use, e.g. compassionate use or named-patient basis, or
− other studies, e.g. pharmacoepidemiology, pharmacoeconomics, intensive monitoring, PMS,
etc.
VI.C.6.2.1.2. Adverse Reaction Data Collected in the EudraVigilance Clinical Trial Module
Only cases of Suspected Unexpected Serious Adverse Reactions (SUSARs), related to investigational
medicinal products studied in clinical trials which fall under the scope of Directive 2001/20/EC (see
VI.C.1), should be reported by the sponsor to the EudraVigilance Clinical Trial Module (EVCTM). The
requirements provided in Chapter II of EudraLex Volume 10 of The Rules Governing Medicinal Products
in the European Union should be applied. The ICSRs should be submitted with the value 'EVCTMPROD'
in the data element ‘Message receiver identifier’ (ICH M2 M.1.6) and should be classified as followed,
in accordance with the EudraVigilance business rules34:
• data element ‘Type of report’ (ICH-E2B(R2) A.1.4):
− report from study; and
• data element ‘Study type in which the reaction(s)/event(s) were observed’ (ICH-E2B(R2) A.2.3.3):
− clinical trials.
VI.C.6.2.2. Preparation of Individual Case Safety Reports
VI.C.6.2.2.1. General principles
The content of each valid ICSR transmitted electronically between all stakeholders should comply with
the legal requirements and guidelines detailed in the Commission Implementing Regulation (EU) No
520/2012 and in VI.C.6.1, particularly:
• the requirements provided in Chapter IV and V of the Commission Implementing Regulation (EU)
No 520/2012;
• the latest version of the ICH-endorsed guide for MedDRA users - MedDRA Term Selection: Points to
Consider Document ;
• the EudraVigilance business rules for the electronic transmission of ICSRs detailed in the Note for
guidance - EudraVigilance Human - Processing of Safety Messages and Individual Case Safety
Reports (ICSRs) (EMA/H/20665/04/Final Rev. 2).
It is recognised that it is often difficult to obtain all the details on a specific case. However, the
complete information (medical and administrative data) for a valid ICSR that is available to the sender
should be reported in a structured manner in the relevant ICH-E2B(R2) data elements (which should
be repeated as necessary when multiple information is available) and in the narrative section (see
34 See Footnote 33.
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VI.C.6.2.2.4). This applies to all types of ICSRs, such as reports with initial information on the case,
follow-up information and cases highlighted for nullification35.
In the situation where it is evident that the sender has not transmitted the complete information
available on the case, the receiver may request the sender to re-transmit the ICSR within 24 hours
with the complete case information in electronic format in accordance with the requirements applicable
for the electronic reporting of ICSRs. This should be seen in the light of the qualitative signal detection
and evaluation activity, where it is important for the receiver to have all the available information on a
case to perform the medical assessment (see VI.C.6.2.4).
Where the suspected adverse reactions reported in a single ICSR impact on the known risk-benefit
balance of a medicinal product, this should be considered as an Emerging Safety Issue (see
VI.C.2.2.6), which should be immediately notified in writing to the competent authorities of the
Member States where the medicinal product is authorised and to the Agency. This is in addition to the
reporting requirements detailed in VI.C.4. A summary of the points of concerns and the action
proposed should be recorded in the ICSR in data element ‘Sender’s comments’ (ICH-E2B(R2) B.5.4).
VI.C.6.2.2.2. Information on suspect, interacting and concomitant medicinal products
The suspect, interacting and/or concomitant active substances/invented names of the reported
medicinal products should be provided in accordance with [IR Art 28 (3) (g) to (i)], the ICH-E2B(R2)
guideline and the EudraVigilance business rules.
The characterisation of medicinal products as suspect, interacting or concomitant is based on the
information provided by primary source.
For combination medicinal products, which contain more than one active substance, each active
substance needs to be reflected individually in the data element ‘Active substance name(s)’ (ICH
E2B(R2) B.4.k.2.2), which needs to be repeated for each active substance contained in the
combination medicinal product.
When the primary source reports a suspect or interacting branded/proprietary medicinal product name
without indicating the active substance(s) of the medicinal product and where the proprietary
medicinal product can be one of two or more possible generics, which have a different composition
depending on the country where the medicinal product is marketed, the ICSR should be populated as
follows:
• data element 'Proprietary medicinal product name' (ICH-E2B(R2) B.4.k.2.1) should be populated
with the proprietary/branded medicinal product name as reported by the primary source;
• data element 'Active substance name(s)' (ICH-E2B(R2) B.4.k.2.2) should be completed with the
active substance(s) that correspond(s) to the composition of the proprietary/branded medicinal
product of the country where the reaction/event occurred.
However if the information is available on:
• the 'Identification of the country where the drug was obtained' (data element ICH E2B(R2)
B.4.k.2.3),
• the 'Authorization/application number' (data element ICH-E2B(R2) B.4.k.4.1),
• the 'Country of authorization/application' (data element ICH-E2B(R2) B.4.k.4.2), and/or
• the 'Batch/lot number' (data element ICH-E2B(R2) B.4.k.3),
35 See also VI.C.6.2.2.10 on nullification of individual cases.
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the composition with regard the active substance(s) of the proprietary medicinal product should be
provided accordingly.
Where the primary source reports a suspect or interacting branded/proprietary medicinal product name
without indicating the pharmaceutical form/presentation of the product and where the
proprietary/branded medicinal product can be one of two or more possible pharmaceutical
forms/presentations, which have different compositions in a country, the ICSR should be populated as
follows:
• data element 'Proprietary medicinal product name' (ICH-E2B(R2) B.4.k.2.1) should be populated
with the medicinal product name as reported by the primary source;
• data element 'Active substance name(s)' (ICH-E2B(R2) B.4.k.2.2) should be completed with those
active substances which are in common to all pharmaceutical forms/presentations in the country of
authorisation.
Where medicinal products cannot be described on the basis of the active substances or the invented
names, for example when only the therapeutic class is reported by the primary source, or in case of
other administered therapies that cannot be structured, this information should only be reflected in the
case narrative (data element ICH-E2B(R2) B.5.1). The data elements ‘Proprietary medicinal product
name’ (ICH-E2B(R2) B.4.k.2.1) and ‘Active substance name(s)’ (ICH-E2B(R2) B.4.k.2.2) should not be
populated. The same applies if a suspected food interaction is reported (e.g. to grapefruit juice).
Where a case of adverse reactions is reported to be related only to a therapeutic class, it is considered
incomplete and does not qualify for reporting (see VI.B.2). Efforts should be made to follow-up the
case in order to collect the missing information regarding the suspected medicinal product (see
VI.B.3).
As regards the reporting of drug interactions, which concerns drug/drug (including biological products),
drug/food, drug/device, and drug/alcohol interactions, the coding of the interaction should be
performed in Section ‘Reactions/Events’ (ICH-E2B(R2) B.2) in line with the latest version of the ICH-
Endorsed Guide for MedDRA Users - MedDRA Term Selection: Points to Consider Document. In
addition, for drug/drug interactions, information on the active substances/proprietary medicinal
product names should be provided in the Section ‘Drug information’ (ICH-E2B(R2) B.4), which should
be characterised as interacting in the data element ‘Characterisation of drug role’ (ICH-E2B(R2)
B.4.k.1).
If the primary source suspects a possible causal role of one of the ingredients (e.g., excipient or
adjuvant) of the suspected medicinal product, this information should be provided in the Section ‘Drug
information’ (ICH-E2B(R2) B.4) as a separate entry in addition to the information given regarding the
suspected medicinal product. This should also be specified in the case narrative (data element ICH-
E2B(R2) B.5.1). If available, tests results (positive or negative) in relation to the causal role of the
suspected ingredient should be included in the section 'Results of tests and procedures relevant to the
investigation of the patient' (ICH E2B(R2) B.3).
VI.C.6.2.2.3. Suspected adverse reactions
All available information as described in [IR Art 28 (3) (j)] shall be provided for each individual case.
The coding of diagnoses and provisional diagnoses with signs and symptoms in the data element
'Reaction/event in MedDRA terminology (Lowest Level Term)' (ICH-E2B(R2) B.2.i.1) should be
performed in line with the latest version of the ICH-Endorsed Guide for MedDRA Users, MedDRA Term
Selection: Points to Consider.
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In practice, if a diagnosis is reported with characteristic signs and symptoms, the preferred option is to
select a term for the diagnosis only and to MedDRA code it in the ICH-E2B(R2) section B.2
'Reaction(s)/event(s)'. If no diagnosis is provided, all reported signs and symptoms should be listed
and MedDRA coded in the ICH-E2B(R2) section B.2 'Reaction(s)/event(s)'. If these signs and
symptoms are typically part of a diagnosis, the diagnosis can be MedDRA coded in addition by
competent authorities in Member States or marketing authorisation holders in the ICH-E2B(R2) data
element B.5.3 ‘Sender's diagnosis/syndrome and/or reclassification of reaction/event'.
If in the narrative other events have been reported, which are not typically signs or symptoms of the
primary source's diagnosis or provisional diagnosis, and those events are suspected to be adverse
reactions, they should also be listed and MedDRA coded in the ICH-E2B(R2) section B.2
'Reaction(s)/event(s)'.
In case a competent authority in a Member State or a marketing authorisation holder disagrees with
the diagnosis reported by the primary source, an alternative diagnosis can be provided in the ICH-
E2B(R2) data element B.5.3 ‘Sender's diagnosis/syndrome and/or reclassification of reaction/event’ in
addition to the reported diagnosis provided in the ICH-E2B(R2) section B.2 'Reaction(s)/event(s)'. In
this situation, a reasoning should be included in the data element ‘Sender’s comments’ (ICH-E2B(R2)
B.5.4) (See VI.C.6.2.2.4).
In the event of death of the patient, the date, cause of death including autopsy-determined causes
shall be provided as available [IR 28 (3) (l)]. If the death is unrelated to the reported suspected
adverse reaction(s) and is linked for example to disease progression, the seriousness criterion of the
ICSR should not be considered as fatal; the recommendation provided in the EudraVigilance Business
Rules should be followed.
VI.C.6.2.2.4. Case narrative, causality assessment and comments
In accordance with [IR Art 28 (3) (m)], a case narrative (data element ICH-E2B(R2) B.5.1) shall be
provided, where possible36, for all cases with the exception of non-serious cases. The information shall
be presented in a logical time sequence, in the chronology of the patient’s experience including clinical
course, therapeutic measures, outcome and follow-up information obtained. Any relevant autopsy or
post-mortem findings shall also be summarised.
The narrative should be presented in line with the recommendations described in Chapter 5.2 of the
ICH-E2D guideline. In this aspect, it should serve as a comprehensive, stand-alone “medical report”
containing all known relevant clinical and related information, including patient characteristics, therapy
details, medical history, clinical course of the event(s), diagnosis, adverse reactions and their
outcomes, relevant laboratory evidence (including normal ranges) and any other information that
supports or refutes the suspected adverse reactions. An example of a standard narrative template is
available in the Report of the CIOMS Working Group V37.
The information provided in the narrative should be consistent with the data appropriately reflected in
all the other relevant ICH-E2B(R2) data elements of the ICSR.
During the interim arrangements (see VI.C.4.1), the case narratives included in the ICSRs submitted
to the competent authorities in Member States by marketing authorisation holders, should not be
modified or deleted when the ICSRs are forwarded to the EudraVigilance database by the competent
authorities.
36 ‘Where possible’ should be interpreted as having received sufficient information from the primary source to prepare a
concise clinical summary of the individual case.
37 Council for International Organizations of Medical Sciences (CIOMS). Current Challenges in Pharmacovigilance: Pragmatic
Approaches (CIOMS V). Geneva: CIOMS; 2001. http://www.cioms.ch/.
http://www.cioms.ch/
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Where available, comments from the primary source on the diagnosis, causality assessment or other
relevant issue, should be provided in the data element ‘Reporter’s comments’ (ICH-E2B(R2) B.5.2).
Competent authorities in Member States and marketing authorisation holders may provide an
assessment of the case and describe a disagreement with, and/or alternatives to the diagnoses given
by the primary source (See VI.C.6.2.2.3). This should be done in the data element ‘Sender’s
comments’ (ICH-E2B(R2) B.5.4), where discrepancies or confusions in the information notified by the
primary source may also be highlighted. Where applicable, a summary of the points of concerns and
actions proposed should also be included in the data element ‘Sender’s comments’ (ICH-E2B(R2)
B.5.4), if the ICSR leads to notification of an Emerging Safety Issue (see VI.C.2.2.6). The degree of
suspected relatedness of each medicinal product to the adverse reaction(s) may be indicated in the
data element ‘Relatedness of drug to reaction(s)/event(s)’ (ICH-E2B(R2) B.4.k.18), which should be
repeated as necessary. This also allows presenting the degree of relatedness from different sources or
with different methods of assessment.
VI.C.6.2.2.5. Test results
Results of tests and procedures relevant to the investigation of the patient shall be provided [IR Art 28
(3) (k)].
As described in the ICH-E2B(R2) guideline, the section B.3 'Results of tests and procedures relevant to
the investigation of the patient' should capture the tests and procedures performed to diagnose or
confirm the reaction/event, including those tests done to investigate (exclude) a non-drug cause, (e.g.,
serologic tests for infectious hepatitis in suspected drug-induced hepatitis). Both positive and negative
results should be reported.
The coding of investigations should be performed in line with the latest version of the ICH-Endorsed
Guide for MedDRA Users, MedDRA Term Selection: Points to Consider. If it is not possible to provide
information on tests and test results in a structured manner, provisions have been made to allow for
the transmission of the information as free text in the data element ICH-E2B(R2) B.3.2. 'Results of
tests and procedures relevant to the investigation'.
VI.C.6.2.2.6. Supplementary information
Key information from supplementary records should be provided in the relevant section of the ICSR,
and their availability should be mentioned in the data element ‘List of documents held by sender’ (ICH-
E2B(R2) A.1.8.2).
Other known case identifiers relevant for the detection of duplicates should be presented
systematically in the data element ‘Other case identifiers in previous transmissions’ (ICH-E2B(R2)
A.1.11).
VI.C.6.2.2.7. Follow-up information
ICSRs are sent at different times to multiple receivers. Therefore the initial/follow-up status is
dependent upon the receiver. For this reason an item to capture follow-up status is not included in the
ICH-E2B(R2) data elements. However, the data element ‘Date of receipt of the most recent information
for this report’ (ICH-E2B(R2) A.1.7) taken together with the data element ‘Sender identifier’ (ICH
E2B(R2) A.3.1.2) and the data element ‘Sender’s (case) report unique identifier’ (ICH-E2B(R2)
A.1.0.1) provide a mechanism for each receiver to identify whether the report being transmitted is an
initial or a follow-up report. For this reason these items are considered critical for each transmission
and a precise date should always be used (i.e. day, month, year). The data element ‘Date of receipt of
the most recent information for this report’ (ICH-E2B(R2) A.1.7) should therefore always be updated
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each time a follow-up information is received by a competent authority or a marketing authorisation
holder, independently whether the follow-up information received is significant enough to be reported.
The data element ‘Date report was first received from the source’ (ICH-E2B(R2) A.1.6) should remain
unchanged to the date the competent authority or the marketing authorisation holder became aware of
the initial report.
New information should be clearly identifiable in the case narrative (data element ICH-E2B(R2) B.5.1)
and provided in a structured format in the applicable ICH-E2B(R2) data elements.
Competent authorities in Member States or marketing authorisation holders should report follow-up
information if significant new medical information has been received. Significant new information
relates to for example new suspected adverse reaction(s), a change in the causality assessment and
any new or updated information on the case that impacts on its medical interpretation. Therefore, the
identification of significant new information requiring to be reported always necessitates medical
judgement.
Situations where the seriousness criteria and/or the causality assessment are downgraded (e.g. follow-
up information leads to a change of the seriousness criteria from serious to non-serious; causality
assessment is changed from related to non-related) should also be considered as significant changes
and thus reported (See VI.B.7.1 for reporting time frames).
In addition, competent authorities in Member States or marketing authorisation holders should also
report follow-up information, where new administrative information is available, that could impact on
the case management; for example, if new case identifiers have become known to the sender, which
may have been used in previous transmissions (data element ‘Other case identifiers in previous
transmissions’ (ICH-E2B(R2) A.1.11)). This information may be specifically relevant to manage
potential duplicates. Another example refers to data element ‘Additional available documents held by
sender’ (ICH-E2B(R2) A.1.8), whereby new documents that have become available to the sender may
be relevant for the medical assessment of the case.
In contrast, a follow-up report which contains non-significant information does not require to be
reported. This may refer, for example, to minor changes to some dates in the case with no implication
for the evaluation or transmission of the case, or corrections of typographical errors in the previous
case version.Medical judgement should be applied since a change to the birth date may constitute a
significant modification (e.g. with implications on the age information of the patient). Similarly, a
change of the status of a MedDRA code/term from current to non-current, due to a version change of
MedDRA, can be considered as a non-significant change as long as this change has no impact on the
medical content of a case. However, an amendment of the MedDRA coding due to a change in the
interpretation of a previously reported suspected adverse reaction may constitute a significant change
and therefore should be reported.
In situations where the case is modified without impacting on its medical evaluation, while no new
follow-up is received (e.g., for correcting a mistake or typographical error), the date of receipt of the
most recent information reported in the data element ‘Date of receipt of the most recent information
for this report’ (ICH-E2B(R2) A.1.7 ) should not be changed. This data element should however be
updated in any other situations, to the date when new follow-up information is received (independently
whether it is significant or not) or to the date when changes are made which impact on the
interpretation of the case.
Where follow-up information of a case initially reported by a marketing authorisation holder is received
directly by a competent authority, the ‘Worldwide unique case identification number’ (ICH-E2B(R2)
A.1.10) of the initial report should be maintained, in adherence with the ICH-E2B(R2) rules. The same
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principle should be applied if a follow-up is received by a marketing authorisation holder of a case
initially reported by a competent authority.
VI.C.6.2.2.8. What to take into account for data privacy laws
To detect, assess, understand and prevent adverse reactions and to identify, and take actions to
reduce the risks of, and increase the benefits from medicinal products for the purpose of safeguarding
public health, the processing of personal data within the EudraVigilance database is possible while
respecting EU legislation in relation to data protection (Directive 95/46/EC, Regulation (EC) No
45/2001).
Where in accordance with applicable national legislation, information related to personal data cannot
be transferred to the EudraVigilance database, pseudonymisation may be applied by competent
authorities in Member States and by marketing authorisation holders, thereby replacing identifiable
personal data such as name and address with pseudonyms or key codes, for example in accordance
with the ISO Technical Specification DD ISO/TS 25237:2008, Health informatics – Pseudonymization
[IR Recital 17]. The application of pseudonymisation will facilitate the ability of the EudraVigilance
system to adequately support case processing and detect duplicates. This should however be done
without impairing the information flow in the EudraVigilance database and the interpretation and
evaluation of safety data relevant for the protection of public health; given the high-level nature of the
information, data elements such as patient's age, age group and gender should in principle be kept un-
redacted/visible.
VI.C.6.2.2.9. Handling of languages
The ICH-E2B(R2) concept for the electronic reporting of ICSRs is based on the fact that structured and
coded information is used for data outputs of pharmacovigilance systems (e.g. listings) and for signal
detection. However, for scientific case assessment and signal evaluation, the medical summary
provided in the data element ‘Case narrative including clinical course, therapeutic measures, outcome
and additional relevant information’ (ICH-E2B(R2) B.5.1) is normally required (see VI.6.2.2.4).
Where suspected adverse reactions are reported in narrative and textual descriptions in an official
language of the Union other than English, the original verbatim text and the summary thereof in
English shall be provided by the marketing authorisation holder. Member States may report case
narratives in their official language(s). For those reports, case translations shall be provided when
requested by the Agency or other Member States for the evaluation of potential signals. For suspected
adverse reactions originating outside the EU, English shall be used in the ICSR [IR 28 (4)].
Additional documents held by the sender, which may be only available in a local language, should only
be translated if requested by the receiver.
VI.C.6.2.2.10. Nullification of cases
In line with the ICH-E2B(R2) guideline, the nullification of individual cases should be used to indicate
that a previously transmitted report should be considered completely void (nullified), for example when
the whole case was found to be erroneous or in case of duplicate reports. It is essential to use the
same case report numbers previously submitted in the data element ‘Sender’s (case) safety report
unique identifier’ (ICH-E2B(R2) A.1.0.1) and in the data element ‘Worldwide unique case identification
number’ (ICH-E2B(R2) A.1.10).
A nullified case is one that should no longer be considered for scientific evaluation. The process of the
nullification of a case is by means of a notification by the sender to the receiver that this is no longer a
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valid case. However, the case should be retained in the sender’s pharmacovigilance database for
auditing purposes.
The principles to be considered when nullifying a case are detailed in VI. Appendix 5.
VI.C.6.2.3. Special situations
VI.C.6.2.3.1. Use of a medicinal product during pregnancy or breastfeeding
General recommendations are provided in VI.B.6.1.
With regard to the electronic reporting of parent-child/foetus cases, the following should be adhered
to:
• In the situation where a foetus or nursing infant is exposed to one or several medicinal products
through the parent and experiences one or more suspected adverse reactions (other than early
spontaneous abortion/foetal demise), information on both the parent and the child/foetus should
be provided in the same report. These cases are referred to as parent-child/foetus reports. The
information provided in the section ‘Patients characteristics’ (ICH-E2B(R2) B.1) applies only to the
child/foetus. The characteristics concerning the parent (mother or father), who was the source of
exposure to the suspect medicinal product should be provided in the data element ‘For a parent-
child/fetus report, information concerning the parent’ (ICH-E2B(R2) B.1.10). If both parents are
the source of the suspect drug(s) then the case should reflect the mother’s information in the data
element ‘For a parent-child/fetus report, information concerning the parent’ (ICH E2B(R2) B.1.10).
The data element ‘Case narrative including clinical course, therapeutic measures, outcome and
additional relevant information’ (ICH-E2B(R2) B.5.1) should describe the entire case, including the
father’s information.
• If both the parent and the child/foetus experience suspected adverse reactions, two separate
reports, i.e. one for the parent (mother or father) and one for the child/foetus, should be created
but they should be linked by using the data element ‘Identification number of the report which is
linked to this report’ (ICH-E2B(R2) A.1.12) in each report.
• If there has been no reaction affecting the child, the parent-child/foetus report does not apply; i.e.
the section ‘Patients characteristics’ (ICH-E2B(R2) B.1) applies only to the parent (mother or
father) who experienced the suspected adverse reaction.
• For those cases describing miscarriage or early spontaneous abortion, only a parent report is
applicable, i.e. the section ‘Patients characteristics’ (ICH-E2B(R2) B.1) apply to the mother.
However, if the suspect medicinal product was taken by the father, the data element ‘Additional
information on drug’ (ICH-E2B(R2) B.4.k.19) should specify that the medication was taken by the
father.
VI.C.6.2.3.2. Suspected adverse reaction reports published in the scientific and medical
literature
EU requirements in relation to the monitoring of suspected drug reactions reported in the scientific and
medical literature are provided in VI.C.2.2.3. With regard to the electronic reporting of ICSRs published
in the scientific and medical literature, the following applies:
• The literature references shall be included in the data element ‘Literature reference(s)’ (ICH-
E2B(R2) A.2.2) in the Vancouver Convention (known as “Vancouver style”), developed by the
International Committee of Medical Journal Editors [IR Art 28 (3) (b)]. The standard format as well
as those for special situations can be found in the following reference: International Committee of
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Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. N
Engl J Med. 1997; 336: 309-15, which is in the Vancouver style38.
• A comprehensive English summary of the article shall be provided in the data element ‘Case
narrative including clinical course, therapeutic measures, outcome and additional relevant
information’ (ICH-E2B(R2) B.5.1) [IR Art 28 (3) (b)].
• Upon request of the Agency, for specific safety review, a full translation in English and a copy of
the relevant literature article shall be provided by the marketing authorisation holder that
transmitted the initial report, taking into account copyright restrictions [IR 28 (3)]. The
recommendations detailed in VI.App2.10, regarding the mailing of the literature article, should be
adhered to.
• Recommendations presented in VI.App2.10, for the reporting of several cases when they are
published in the same literature article, should be followed.
VI.C.6.2.3.3. Suspected adverse reactions related to overdose, abuse, off-label use, misuse,
medication error or occupational exposure
General principles are provided in VI.B.6.3.
If a case of overdose, abuse, off-label use, misuse, medication error or occupational exposure is
reported with clinical consequences, the MedDRA Lowest Level Term code, corresponding to the term
closest to the description of the reported overdose, abuse, off-label use, misuse, medication error or
occupational exposure should be added to the observed suspected adverse reaction(s) in the data
element ‘Reaction/event in MedDRA terminology (Lowest Level Term)’ (ICH-E2B(R2) B.2.i.1), in line
with recommendations included in the latest version of the ICH-Endorsed Guide for MedDRA Users
'MedDRA Term Selection: Points to Consider'.
VI.C.6.2.3.4. Lack of therapeutic efficacy
General principles are provided in VI.B.6.4.
If the primary source suspects a lack of therapeutic efficacy, the MedDRA Lowest Level Term code,
corresponding to the term closest to the description of the reported lack of therapeutic efficacy, should
be provided in the data element ‘Reaction/event in MedDRA terminology (Lowest Level Term)’ (ICH-
E2B(R2) B.2.i.1), in line with recommendations included in the latest version of the ICH-Endorsed
Guide for MedDRA Users 'MedDRA Term Selection: Points to Consider'.
Unless aggravation of the medical condition occurs, the indication for which the suspected medicinal
product was administered should not be included in the data element ‘Reaction/event in MedDRA
terminology (Lowest Level Term).
The same reporting modalities as for serious ICSRs (See VI.C.4) should be applied for those cases
related to classes of medicinal products where, as described in VI.B.6.4, reports of lack of therapeutic
efficacy should be reported within a 15-day time frame. If no seriousness criterion is available, it is
acceptable to submit the ICSR within 15 days as non-serious.
38 The Vancouver recommendations are also available on the International Committee of Medical Journal Editors website
http://www.icmje.org.
http://www.icmje.org/
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VI.C.6.2.3.5. Suspected adverse reactions related to quality defect or falsified medicinal
products
EU requirements are provided in VI.C.2.2.4. In order to be able to clearly identify cases related to
quality defect or falsified medicinal products when they are exchanged between stakeholders, the
following recommendations should be applied:
a. Quality defect
Where a report of suspected adverse reactions is associated with a suspected or confirmed quality
defect of a medicinal product, the MedDRA Lowest Level Term code of the term corresponding most
closely to the product quality issue, should be added to the observed suspected adverse reaction(s) in
the data element ‘Reaction/event in MedDRA terminology (Lowest Level Term)’ (ICH-E2B(R2) B.2.i.1).
b. Falsified medicinal products
Where a report of suspected adverse reactions is associated with a suspected or confirmed falsified39
ingredient, active substance or medicinal product, the MedDRA Lowest Level Term code of the term
corresponding most closely to the reported information should be added to the observed suspected
adverse reaction(s) in the data element ‘Reaction/event in MedDRA terminology (Lowest Level Term)’
(ICH-E2B(R2) B.2.i.1). Information on the suspected medicinal product, active substance(s) or
excipient(s) should be provided in the data elements ‘Proprietary medicinal product name’ (ICH-
E2B(R2) B.4.k.2.1) and/or ‘Active substance name(s)’ (ICH-E2B(R2) B.4.k.2.2) as reported by the
primary source.
VI.C.6.2.3.6. Suspected transmission via a medicinal product of an infectious agent
EU requirements are provided in VI.C.2.2.5.
The coding of a suspected transmission of an infectious agent via a medicinal product in the data
element 'Reaction/event in MedDRA terminology (Lowest Level Term)' (ICH-E2B(R2) B.2.i.1 ) should
be performed in line with the latest version of the ICH-Endorsed Guide for MedDRA Users 'MedDRA
Term Selection: Points to Consider'.
In addition, if the infectious agent is specified, the MedDRA Lowest Level Term code corresponding to
the infectious agent should also be included in the data element ‘Reaction/event in MedDRA
terminology (Lowest Level Term)’ (ICH-E2B(R2) B.2.i.1).
VI.C.6.2.3.7. Reports originating from organised data collection systems and other systems
General safety reporting requirements in the EU for post-authorisation studies are provided in VI.C.1
and VI.C.2.2.2. Individual case safety reports originating from those studies shall contain information
on study type, study name and the sponsor’s study number or study registration number [IR Art 28
(3)(c)]. This should be provided in ICH E2B(R2) section A.2.3 ‘Study identification’.
Safety reporting requirements regarding patient support programmes or market research programmes
are provided in VI.C.2.2.11.
The following reporting rules should be applied based on (i) the type of data collection system and (ii)
whether the suspected medicinal product is part of the scope of the data collection system.
1. For all patient support programmes, non-interventional studies with primary data collection from
consumers and healthcare professionals, and for certain compassionate use or named patient use
where adverse events are actively sought:
39 As presented in EU legislation (Directive 2011/62/EU).
http://ec.europa.eu/health/files/eudralex/vol-1/dir_2011_62/dir_2011_62_en.pdf
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a) Where the adverse reaction is suspected to be related at least to the studied (or supplied)
medicinal product:
• the report should be considered as solicited;
• the ICH E2B(R2) data element A.1.4 'Type of report' should be populated with the value 'Report
from study';
• the ICH E2B(R2) data element A.2.3.3 'Study type in which the reaction(s)/event(s) were
observed' should be populated with the value ‘Other studies’ or 'Individual patient use'.
b) Where the adverse reaction is only suspected to be related to a medicinal product which is not
subject to the scope of the organised data collection system and there is no interaction with the
studied (or supplied) medicinal product:
• the report should be considered as spontaneous report; as such it conveys the suspicion of the
primary source;
• The ICH E2B(R2) data element A.1.4 'Type of report' should be populated with the value
'Spontaneous'.
2. For certain compassionate use or named patient use where adverse event reporting is not solicited:
• the report should be considered as spontaneous report; as such it conveys the suspicion of the
primary source;
• The ICH E2B(R2) data element A.1.4 'Type of report' should be populated with the value
'Spontaneous'.
3. For clinical trial conducted in accordance with Directive 2001/20/EC and where the adverse reaction
is only suspected to be related to a non-investigational medicinal product (or another medicinal
product which is not subject to the scope of the clinical trial) and there is no interaction with the
investigational medicinal product:
• the report should be considered as spontaneous report; as such it conveys the suspicion of the
primary source;
• The ICH E2B(R2) data element A.1.4 'Type of report' should be populated with the value
'Spontaneous'.
All ICSRs which are reportable to the EudraVigilance database and which originate from post-
authorisation studies which do not fall under the scope of the clinical trials Directive 2001/20/EC,
should be submitted to EVPM (see VI.C.6.2.1). The same applies to cases of adverse reactions
originating in clinical trials if they are not suspected to be related to the investigational medicinal
product.
VI.C.6.2.3.8. Receipt of missing minimum information
When missing minimum information (See VI.B.2) has been obtained about a non-valid ICSR, the
following rules should be applied:
• the data element ‘Date report was first received from source’ (ICH-E2B(R2) A.1.6) should contain
the date of receipt of the initial non-valid ICSR;
• the data element ‘Date of receipt of the most recent information for this report’ (ICH-E2B(R2)
A.1.7) should contain the date when all the four elements of the minimum information required for
reporting have become available;
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• clarification should be provided in the case narrative (data element ICH-E2B(R2) B.5.1) that some
of the four elements were missing in the initial report.;
• as for any reported cases, compliance monitoring is performed against the data element ‘Date of
receipt of the most recent information for this report’ (ICH-E2B(R2) A.1.7).
VI.C.6.2.4. Data quality of individual case safety reports transmitted electronically and
duplicate management
The EudraVigilance database should contain all cases of suspected adverse reactions that are
reportable according to Directive 2001/83/EC and Regulation (EC) No 726/2004 to support
pharmacovigilance activities. This applies to all medicinal products authorised in the EU independent of
their authorisation procedure.
The EudraVigilance database should also be based on the highest internationally recognised data
quality standards.
To achieve these objectives, all competent authorities in Member States and marketing authorisation
holders should adhere to:
• the electronic reporting requirements as defined in EU legislation;
• the concepts of data structuring, coding and reporting in line with the EU legislation, guidelines,
standards and principles referred to in VI.C.6.2.2.1.
This is a pre-requisite to maintain a properly functioning EudraVigilance database intended to fully
support the protection of public health.
The Agency shall, in collaboration with the stakeholder that submitted an ICSR to the EudraVigilance
database, be responsible for operating procedures that ensure the highest quality and full integrity of
the information collected in the EudraVigilance database [REG Art 24(3)]. This includes as well the
monitoring of use of the terminologies referred to in Chapter IV of the Commission Implementing
Regulation (EU) No 520/2012 [IR Art 25(3)].
Specific quality system procedures and processes shall be in place in order to ensure
• the submission of accurate and verifiable data on serious and non-serious suspected adverse
reactions to the Eudravigilance database within the 15 or 90-day time frame [IR Art 11 (1) (c)],
• the quality, integrity and completeness of the information submitted on the risks of medicinal
products, including processes to avoid duplicate submissions [IR Art 11 (1) (d)].
In this regard, marketing authorisation holders and competent authorities in Member States should
have in place an audit system, which ensures the highest quality of the ICSRs transmitted
electronically to the EudraVigilance database within the correct time frames, and which enables the
detection and management of duplicate ICSRs in their system. Those transmitted ICSRs should be
complete, entire and undiminished in their structure, format and content.
High level business process maps and process descriptions in relation to the quality review of ICSRs
and the detection and management of duplicate ICSRs are provided in VI. Appendix 6 and VI.
Appendix 7. Further guidance on the detection of duplicate ICSRs is available in the Guideline on the
Detection and Management of Duplicate Individual Cases and Individual Case Safety Reports (ICSRs),
EMA/13432/2009.
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/06/WC500129037.pdf
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A review of the ICSRs quality, integrity and compliance with the reporting time frames will be
performed by the Agency at regular intervals for all organisations reporting to the EudraVigilance
database. Feedback from these reviews will be provided to those organisations.
VI.C.6.2.5. Electronic re-transmission of ICSRs between multiple senders and receivers
The electronic re-transmission of cases refers to the electronic exchange of ICSRs between multiple
senders and receivers, for example where in case of contractual agreement, a third country ICSR is
first reported by a marketing authorisation holder outside the EU to another marketing authorisation
holder in the EU and from there to the Agency. This applies as well for the interim arrangements
period, where based on the reporting requirements detailed in VI.C.4.1, ICSRs originating in the EU are
submitted by marketing authorisation holders to the competent authorities in the Member State where
the reaction occurred and then re-transmitted to the EudraVigilance database.
During this re-transmission process, information on the case should not in principle be omitted or
changed if no new information on the case is available to the re-transmitting sender.
Exceptions apply to the following data elements or sections:
• ‘Sender’s (case) safety report unique identifier’ (ICH-E2B(R2) A.1.0.1);
• ‘Date of this transmission’ (ICH-E2B(R2) A.1.3);
• ‘Date report was first received from source’ (ICH-E2B(R2) A.1.6), for initial reports;
• ‘Date of receipt of the most recent information for this report’ (ICH-E2B(R2) A.1.7);
• ‘Information on sender and receiver of case safety report’ (ICH-E2B(R2) A.3);
• ‘Relatedness of drug to reaction(s)/event(s)’ (ICH-E2B(R2) B.4.k.18);
• ‘Sender's diagnosis/syndrome and/or reclassification of reaction/event’ (ICH-E2B(R2) B.5.3);
• ‘Sender’s comments’ (ICH-E2B(R2) B.5.4).
In the interest of improving data quality, in case of errors or inconsistencies in the report, the re-
transmitters should go back to the originator of the report to correct the case accordingly. However, if
this cannot be done within normal reporting time frame, the re-transmitter can correct information that
has been incorrectly structured.
In addition, any electronic data interchange partner should adhere to the ICH-E2B(R2) rules regarding
the provision of follow-up information, whereby the ‘Worldwide unique case identification number’
(ICH-E2B(R2) A.1.10) should be maintained in accordance with the ICH-E2B(R2) guideline. Non-
adherence to these administrative requirements endangers the electronic case management and leads
to the potential for unnecessary duplication of reports in the receiver’s database.
VI.C.6.2.6. Electronic reporting through company’s headquarters
If a pharmaceutical company decides to centralise the electronic reporting of ICSRs (e.g. by reporting
through the company’s global or EU headquarter), the following should be taken into account:
• the central reporting arrangement should be clearly specified in the marketing authorisation
holder’s pharmacovigilance system master file and in the internal standard operating procedures;
• the company’s headquarter designated for reporting the ICSRs should be registered with
EudraVigilance;
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• the same principles may be applied for reporting ICSRs from the competent authorities in Member
States to the marketing authorisation holders during the interim arrangements period, that is the
competent authorities in Member States report electronically to the company’s headquarter instead
of to the local affiliates.
VI.C.6.3. Electronic submission of information on medicinal products
To support the objectives of Directive 2001/83/EC and Regulation (EC) No 726/2004, the provisions
provided in second sub-paragraph of Article 57(2) of Regulation (EC) No 726/2004, regarding the
electronic submission and update of information on medicinal products for human use authorised or
registered in the EU, shall be followed by marketing authorisation holders. In this aspect marketing
authorisation holders shall apply the internationally agreed formats and terminologies described in
Chapter IV of the Commission Implementing Regulation (EU) No 520/2012. Recommendations related
to the electronic submission of information on medicines are provided on the Agency’s website40.
40 EMA documents for electronic submission of information on medicines
(http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000336.jsp&murl=
menus/regulations/regulations.jsp&mid=WC0b01ac0580410138&jsenabled=true)
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000336.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac0580410138&jsenabled=true
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000336.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac0580410138&jsenabled=true
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VI. Appendix 1 Identification of biological medicinal
products41
Figure VI.2. Business process map - Identification of biological medicinal products
41 Mandatory when they are the subject of reports of suspected adverse reactions [DIR Art 102(e) and IR Art 28 (3)].
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Table VI.1. Process description - Identification of biological medicinal products
No. Step Description Responsible
Organisation
1 Start.
Receive report.
Day 0. Receipt of the information for
the case that indicates that one of the
suspect drugs is of biological origin.
MAH/NCA
2 Does report concern a biological
medicinal product?
If Yes, go to step 3
If No, go to step 4
3 Are batch number, brand name
& active substance all present
and identifiable?
If Yes, create the case and send it to the
correct receiver (step 3).
If there is more than one batch number,
structure the batch number that coincided
with the adverse reaction in the Drug
section (ICH-E2B(R2) B.4) and enter the
other batch numbers in the case narrative.
If No, create the case and send it to the
correct receiver (step 3) and follow-up
with the reporter (step 3.1).
MAH/NCA
3.1 Follow-up with reporter. Follow-up with the reporter to attempt to
identify the missing information.
MAH/NCA
3.2 Was reporter able to provide the
missing information?
If Yes, return to step 1 – the information
should be treated as follow-up and a new
version created & transmitted.
If No, document this (step 3.3).
MAH/NCA
3.3 Document the required missing
information in the case.
Document in the case that the missing
required information has been sought but
the reporter was not able or willing to
provide it.
MAH/NCA
4 Send to receiver, where
applicable.
If the case requires transmission to a
receiver, transmit the case electronically,
in E2B(R2) format within the relevant
timelines (15 or 90 days), to the relevant
receiver.
MAH/NCA
5 Receive in DataBase (DB). Receive the case electronically and load it
into the pharmacovigilance database.
Receiver
6 Validate products and
substances
Validate the products and substances to
ensure that the brand name, active
substance & batch number are all present
and identifiable.
This validation should be complementary
to the usual business rules validations.
Receiver
7 Was validation successful? If Yes, store the case in the
pharmacovigilance database (step 8).
If No, contact the sender (Step 7.1).
Receiver
7.1 Contact sender. Contact the sender regarding the missing
or not identifiable information.
Receiver
7.2 Is required data in the case Upon receipt of communication from the MAH/NCA
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No. Step Description Responsible
Organisation
file? receiver, check in the case file to see if the
missing or unidentifiable information is
already on file.
If it is on file, correct the case (step 7.3).
If the information is not on file, contact
the reporter to request the missing
information (step 3.1).
7.3 Correct case. Correct the case to include the missing
information & send updated version to
receiver (step 4).
MAH/NCA
8 Store case in
PharmacoVigilance DataBase
(PhV DB).
The case should now be stored in the
pharmacovigilance database.
Receiver
9 End. The case is now available for signal
detection and data quality analyses.
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VI. Appendix 2 Detailed guidance on the monitoring of
scientific and medical literature
VI. App2.1 When to start and stop searching in the scientific and medical
literature
EU specific requirements, as regards the monitoring of scientific and medical literature are provided in
VI.C.2.2.3.
In addition to the reporting of serious and non-serious ICSRs or their presentation in periodic safety
update reports, the marketing authorisation holder has an obligation to review the worldwide
experience with medicinal product in the period between the submission of the marketing authorisation
application and the granting of the marketing authorisation. The worldwide experience includes
published scientific and medical literature. For the period between submission and granting of a
marketing authorisation, literature searching should be conducted to identify published articles that
provide information that could impact on the risk-benefit assessment of the product under evaluation.
For the purpose of the preparation of periodic safety update reports (See Module VII) and the
notification of Emerging Safety Issues (See VI.C.2.2.6), the requirement for literature searching is not
dependent on a product being marketed. Literature searches should be conducted for all products with
a marketing authorisation, irrespective of commercial status. It would therefore be expected that
literature searching would start on submission of a marketing authorisation application and continue
while the authorisation is active.
VI. App2.2 Where to look
Articles relevant to the safety of medicinal products are usually published in well-recognised scientific
and medical journals, however, new and important information may be first presented at international
symposia or in local journals. Although the most well-known databases (e.g. Medline) cover the
majority of scientific and medical journals, the most relevant publications may be collated elsewhere in
very specialised medical fields, for certain types of product (e.g. herbal medicinal products) or where
safety concerns are subject to non-clinical research. A marketing authorisation holder should establish
the most relevant source of published literature for each product.
Medline, Embase and Excerpta Medica are often used for the purpose of identifying ICSRs. These
databases have broad medical subject coverage. Other recognised appropriate systems may be used.
The database providers can advise on the sources of records, the currency of the data, and the nature
of database inclusions. It is best practice to have selected one or more databases appropriate to a
specific product. For example, in risk-benefit assessment, safety issues arising during non-clinical
safety studies may necessitate regular review of a database that has a less clinical focus and includes
more laboratory-based publications.
Relevant published abstracts from meetings and draft manuscripts should be reviewed for reportable
ICSRs and for inclusion in periodic safety update reports. Although it is not a requirement for
marketing authorisation holders to attend all such meetings, if there are company personnel at such a
meeting, or it is sponsored by a marketing authorisation holder, it is expected that articles of relevance
would be available to the marketing authorisation holder's pharmacovigilance system. In addition,
literature that is produced or sponsored by a marketing authorisation holder should be reviewed, so
that any reportable ICSRs can be reported as required in advance of publication.
If ICSRs are brought to the attention of a marketing authorisation holder from this source, they should
be processed in the same way as ICSRs found on searching a database or reviewing a journal.
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Abstracts from major scientific meetings are indexed and available in some databases, but posters and
communications are rarely available from this source.
VI. App2.3 Database Searches
A search is more than a collection of terms used to interrogate a database. Decisions about the
database selection, approach to records retrieval, term or text selection and the application of limits
need to be relevant to the purpose of the search. For searches in pharmacovigilance, some of the
considerations for database searching are described below.
VI. App2.3.1 Precision and recall
Medical and scientific databases are a collection of records relating to a set of publications. For any
given record, each database has a structure that facilitates the organisation of records and searching
by various means, from simple text to complex indexing terms with associated subheadings. Search
terms (text or indexed) can be linked using Boolean operators and proximity codes to combine
concepts, increasing or decreasing the specificity of a search. In addition, limits to the output can be
set. When searching, the application of search terms means that the output is less than the entire
database of the records held. The success of a search can be measured according to precision and
recall (also called sensitivity). Recall is the proportion of records retrieved ("hits") when considering
the total number of relevant records that are present in the database. Precision is the proportion of
"hits" that are relevant when considering the number of records that were retrieved. In general, the
higher recall searches would result in low precision.
VI. App2.3.2 Search construction
Databases vary in structure, lag time in indexing and indexing policy for new terms. While some
database providers give information about the history of a particular indexing term or the application
of synonyms, other databases are less sophisticated. In addition, author abstracts are not always
consistent in the choice of words relating to pharmacovigilance concepts or medicinal products/active
substances names.
When constructing a search for pharmacovigilance, the highest recall for a search would be to enter
the medicinal product name and active substance name (in all their variants) only. In practice,
additional indexing terms and text are added to increase precision and to reduce the search result to
return records that are of relevance to pharmacovigilance. There is a balance to be achieved. It is,
therefore, expected that complicated searches are accompanied by initial testing to check that relevant
records are not omitted, however, there is no defined acceptable loss of recall when searching for
pharmacovigilance purposes. Term selection should be relevant to the database used and the subject
of the search.
VI. App2.3.3 Selection of product terms
Searches should be performed to find records for active substances and not for brand names only. This
can also include excipients or adjuvants that may have a pharmacological effect. When choosing
search terms for medicinal products, there are a number of considerations.
• Is the active substance an indexed term?
• What spellings might be used by authors (particularly if the active substance is not indexed)?
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• What alternative names might apply (numbers or codes used for products newly developed,
chemical names, brand names, active metabolites)?
• Is it medically relevant to search only for a particular salt or specific compound for an active
substance?
During searches for ICSRs, it may be possible to construct a search that excludes records for
pharmaceutical forms or routes of administration different to that of the subject product, however,
restrictions should allow for the inclusion of articles where this is not specified. Search construction
should also allow for the retrieval of overdose, medication error, abuse, misuse, off-label use or
occupational exposure information, which could be poorly indexed. Searches should also not routinely
exclude records of unbranded products or records for other company brands.
VI. App2.3.4 Selection of search terms
As described previously, there is no acceptable loss of recall when searching published literature for
pharmacovigilance. The use of search terms (free text or use of indexing) to construct more precise
searches may assist in managing the output. Deficiencies that have been found frequently during
Competent Authority inspections include:
• the omission of outcome terms, for example "death" as an outcome may be the only indexed term
in a case of sudden death;
• the omission of pregnancy terms to find adverse outcomes in pregnancy for ICSR reporting;
• the omission of terms to include special types of reports which needs to be addressed as well in
periodic safety update reports, for example,
− Reports of asymptomatic overdose, medication error, off-label use, misuse, abuse,
occupational exposure;
− Reports of uneventful pregnancy.
VI. App2.3.5 Limits to a search
Some databases apply indexing that allows the application of limits to a search, for example by subject
age, sex, publication type. The limits applied to a search are not always shown in the "search strategy"
or search string.
If limits are applied, they should be relevant to the purpose of the search. When searching a worldwide
scientific and medical literature database, titles and abstracts are usually in English language. The use
of limits that reduce the search result to only those published in the English language is generally not
acceptable. Limits applied to patient types, or other aspects of an article, for example human, would
need to be justified in the context of the purpose of a search.
Limits can be applied to produce results for date ranges, for example, weekly searches can be obtained
by specifying the start and end date for the records to be retrieved. Care should be taken to ensure
that the search is inclusive for an entire time period, for example, records that may have been added
later in the day for the day of the search should be covered in the next search period. The search
should also retrieve all records added in that period, and not just those initially entered or published
during the specified period (so that records that have been updated or retrospectively added are
retrieved). This should be checked with the database provider if it is not clear.
Although one of the purposes of searching is to identify ICSRs for reporting, the use of publication type
limits is not robust. ICSRs may be presented within review or study publications, and such records may
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not be indexed as "case-reports", resulting in their omission for preparation of periodic safety update
reports from search results limited by publication type.
VI. App2.4 Record keeping
Records of literature searches should be maintained in accordance with the requirements described in
[IR Art 12]. Marketing authorisation holders should demonstrate due diligence in searching published
scientific and medical literature. It is always good practice to retain a record of the search construction,
the database used and the date the search was run. In addition, it may be useful to retain results of
the search for an appropriate period of time, particularly in the event of zero results. If decision
making is documented on the results, it is particularly important to retain this information.
VI. App2.5 Outputs
Databases can show search results in different ways, for example, titles only or title and abstract with
or without indexing terms. Some publications are of obvious relevance at first glance, whereas others
may be more difficult to identify. Consistent with the requirement to provide the full citation for an
article and to identify relevant publications, the title, citation and abstract (if available) should always
be retrieved and reviewed.
VI. App2.6 Review and selection of articles
It is recognised that literature search results are a surrogate for the actual article. Therefore, it is
expected that the person reviewing the results of a search is trained to identify the articles of
relevance. This may be an information professional trained in pharmacovigilance or a
pharmacovigilance professional with knowledge of the database used. Recorded confirmation that the
search results have been reviewed will assist in demonstrating that there is a systematic approach to
collecting information about suspected adverse reactions from literature sources. It is recommended
that quality control checks are performed on a sample of literature reviews / selection of articles to
check the primary reviewer is identifying the relevant articles.
A common issue in selecting relevant articles from the results of a search is that often this process is
conducted for the purposes of identification of ICSRs only. Whereas the review should also be used as
the basis for collating articles for the periodic safety update report production, therefore relevant
studies with no ICSRs should also be identified, as well as those reports of events that do not qualify
for reporting.
Outputs from searches may contain enough information to be a valid ICSR, in which case the article
should be ordered. All articles for search results that are likely to be relevant to pharmacovigilance
requirements should be obtained, as they may contain valid ICSRs or relevant safety information. The
urgency with which this occurs should be proportionate to the content of the material reviewed and the
resulting requirement for action as applicable for the marketing authorisation holder.
Articles can be excluded from reporting by the marketing authorisation holder if another company's
branded medicinal product is the suspected medicinal product. In the absence of a specified medicinal
product source and/or invented name, ownership of the medicinal product should be assumed for
articles about an active substance. Alternative reasons for the exclusion of a published article for the
reporting of ICSRs are detailed in VI.C.2.2.3.
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VI. App2.7 Day zero
As described in VI.B.7, day zero is the date on which an organisation becomes aware of a publication
containing the minimum information for an ICSR to be reportable. Awareness of a publication includes
any personnel of that organisation, or third parties with contractual arrangements with the
organisation. It is sometimes possible to identify the date on which a record was available on a
database, although with weekly literature searching, day zero for a reportable adverse reaction present
in an abstract is taken to be the date on which the search was conducted. For articles that have been
ordered as a result of literature search results, day zero is the date when the minimum information for
an ICSR to be valid is available. Organisations should take appropriate measures to obtain articles
promptly in order to confirm the validity of a case.
VI. App2.8 Duplicates
Consistent with the requirements for reporting ICSRs, literature cases should be checked to prevent
reporting of duplicates, and previously reported cases should be identified as such when reported. It is,
therefore, expected that ICSRs are checked in the organisation database to identify literature articles
that have already been reported.
VI. App2.9 Contracting out Literature Search Services
It is possible to use the services of another party to conduct searches of the published scientific and
medical literature. In this event, the responsibility for the performance of the search and subsequent
reporting still remains. The transfer of a pharmacovigilance task or function should be detailed in a
contract between the organisation and the service provider. The nature of third party arrangements for
literature searching can range from access to a particular database interface only (access to a
technology) to full literature searching, review and reporting (using the professional pharmacovigilance
services of another organisation). It is recognised that more than one organisation may share services
of a third party to conduct searches for generic active substances. In this instance, each organisation
should satisfy itself that the search and service is appropriate to their needs and obligations.
Where an organisation is dependent on a particular service provider for literature searching, it is
expected that an assessment of the service(s) is undertaken to determine whether it meets the needs
and obligations of the organisation. In any case, the arrangement should be clearly documented.
The clock start for the reporting of ICSRs begins with awareness of the minimum information by either
the organisation or the contractual partner (whichever is the earliest). This also applies where a third
party provides a review or a collated report from the published scientific and medical literature, in
order to ensure that published literature cases are reported as required within the correct time frames.
That is, day zero is the date the search was run if the minimum criteria are available in the abstract
and not the date the information was supplied to the organisation.
VI. App2.10 Electronic submission of copies of articles published in the
scientific and medical literature
Until standards for the electronic transmission of attachments (e.g. copies of literature articles) are
developed in the framework of ICH, the sender should follow the rules outlined below for the
submission of a copy of the literature article as detailed in VI.C.6.2.3.2:
1. Mailing address and format of literature articles:
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Literature articles reportable to the Agency should be provided in PDF format and sent via e-mail to
the following e-mail address: EVLIT@ema.europa.eu.
In relation to copies of articles from the published scientific and medical literature, marketing
authorisation holders are recommended to consider potential copyright issues specifically as
regards the electronic transmission and handling of electronic copies in the frame of regulatory
activities.
2. File name of literature articles sent in electronic format to the Agency:
The file name of a literature article sent in PDF format should match exactly the ‘World-Wide
Unique Case Identification Number’ (ICH-E2B(R2) A.1.10.1 or A.1.10.2 as applicable) assigned to
the individual case, which is described in the article and which is reported in the E2B(R2) ICSR
format.
If there is a follow-up article to the individual case published in the literature, the file name with
the World-Wide Unique Case Identification Number must be maintained but should include a
sequence number separated with a dash.
Examples:
• Initial ICSR published in the literature: FR-ORGABC-23232321 (data element ‘World-Wide Unique
Case Identification Number’ (ICH-E2B(R2) A.1.10.1));
− File name of the literature article: FR-ORGABC-23232321.pdf.
• Follow-up information published in the literature in a separate article:
− ICSR: FR-ORGABC-23232321 (data element World-Wide Unique Case Identification Number
remains unchanged (ICH-E2B(R2) A.1.10.1));
− File name: FR-ORGABC-23232321-1.pdf.
3. Reporting of cases reported in the scientific and medical literature referring to more than one
patient:
When the literature article refers to the description of more than one patient, the copy of the
literature article should be sent only once.
The file name of a literature article sent in PDF format should match exactly the ‘World-Wide
Unique Case Identification Number’ (data element ICH-E2B(R2) A.1.10.1 or A.1.10.2 as applicable)
assigned to the first reportable individual case described in the article.
In addition, all ICSRs which relate to the same literature article should be cross referenced in the
data element ‘Identification number of the report which is linked to this report’ (ICH-E2B(R2)
A.1.12). The data element should be repeated as necessary to cross refer all related cases (see
Table VI.2).
mailto:EVLIT@ema.europa.eu
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Table VI.2. Examples for the reporting of ICSRs described in the scientific and medical literature and
referring to more than one patient
Ex. Scenario Action
1 A literature article describes
suspected adverse reactions that
have been experienced by up to
3 single patients.
3 ICSRs should be created and
reported for each individual
identifiable patient described in
the literature article.
Each ICSR should contain all the
available information on the
case.
For Case 1 described in the literature article:
• ICH-E2B(R2) A.1.10.1 ‘World-Wide Unique Case
Identification Number’:
UK-ORGABC-0001
• ICH-E2B(R2) A.1.12 ‘Identification number of the report
which is linked to this report’:
UK-ORGABC-0002
• ICH-E2B(R2) A.1.12 ‘Identification number of the report
which is linked to this report’:
UK-ORGABC-0003
• ICH-E2B(R2) A.2.2 ‘Literature reference(s):
Literature reference in line with uniform requirements for
manuscripts submitted to biomedical journals:
N Engl J Med. 1997;336:309-15.
• File name for the copy of literature article to be sent via
e-mail to EVLIT@ema.europa.eu:
UK-ORGABC-0001.pdf
For Case 2 described in the literature article:
• ICH-E2B(R2) A.1.10.1 ‘World-Wide Unique Case
Identification Number’:
UK-ORGABC-0002
• ICH-E2B(R2) A.1.12 ‘Identification number of the report
which is linked to this report’:
UK-ORGABC-0001
• ICH-E2B(R2) A.1.12 ‘Identification number of the report
which is linked to this report’:
UK-ORGABC-0003
• ICH-E2B(R2) A.2.2 ‘Literature reference(s):
Literature reference in line with uniform requirements for
manuscripts submitted to biomedical journals:
N Engl J Med. 1997;336:309-15.
• No copy of the literature article required since the copy
was already submitted for case 1.
For Case 3 described in the literature article:
• ICH-E2B(R2) A.1.10.1 ‘World-Wide Unique Case
Identification Number’:
UK-ORGABC-0003
• ICH-E2B(R2) A.1.12 ‘Identification number of the report
which is linked to this report’:
UK-ORGABC-0001
• ICH-E2B(R2) A.1.12 ‘Identification number of the report
which is linked to this report’:
UK-ORGABC-0002
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Ex. Scenario Action
• ICH-E2B(R2) A.2.2 ‘Literature reference(s):
Literature reference in line with uniform requirements for
manuscripts submitted to biomedical journals:
N Engl J Med. 1997;336:309-15.
• No copy of the literature article required since the copy
was already submitted for case 1.
2 A literature article describes
suspected adverse reactions that
have been experienced by more
than 3 single patients.
ICSRs should be created and
reported for each individual
identifiable patient described in
the literature article.
Each ICSR should contain all the
available information on the
case.
The cross reference with all the
linked ICSRs from this literature
article should only be provided in
the first case, in the data
element ICH-E2B(R2) A.1.12
‘Identification number of the
report which is linked to this
report’. There is no need to
repeat all the cross references in
the other ICSRs.
For the ICSRs which relate to the same literature article, the
cross reference in the data element ‘Identification number of
the report which is linked to this report’ ICH (E2B(R2) field
A.1.12) should be conducted as follows:
• The first case should be linked to all other cases related
to the same article;
• All the other cases should be only linked to the first one,
as in the example below.
Example for the reporting of cases originally reported in the
scientific and medical literature referring to a large number
of patients:
For Case 1 described in the literature article:
• ICH E2B(R2) A.1.10.1 ‘Worldwide Unique Case
Identification Number’:
UK-ORGABC-0001
• ICH-E2B(R2) A.1.12 ‘Identification number of the report
which is linked to this report’:
UK-ORGABC-0002
• ICH-E2B(R2) A.1.12 ‘Identification number of the report
which is linked to this report’:
UK-ORGABC-0003
• ICH-E2B(R2) A.1.12 ‘Identification number of the report
which is linked to this report’:
UK-ORGABC-0004
• ICH-E2B(R2) A.1.12 ‘Identification number of the report
which is linked to this report’:
UK-ORGABC-000N
• ICH-E2B(R2) A.2.2 ‘Literature reference(s)’:
N Engl J Med. 1997;336:309-15.
• File name for the copy of literature article to be sent via
e-mail to EVLIT@ema.europa.eu:
UK-ORGABC-0001.pdf.
For Case 2 described in the literature article:
• ICH E2B(R2) A.1.10.1 ‘Worldwide Unique Case
Identification Number’:
UK-ORGABC-0002
• ICH-E2B(R2) A.1.12 ‘Identification number of the report
which is linked to this report’:
UK-ORGABC-0001
• ICH-E2B(R2) A.2.2 ‘Literature reference(s)’:
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Ex. Scenario Action
N Engl J Med. 1997;336:309-15.
• No copy of the literature article required since the copy
was already submitted for case 1.
For Case N described in the literature article:
• ICH-E2B(R2) A.1.10.1 ‘Worldwide Unique Case
Identification Number’:
UK-ORGABC-000N
• ICH-E2B(R2) A.1.12 ‘Identification number of the report
which is linked to this report’:
UK-ORGABC-0001
• ICH-E2B(R2) A.2.2 ‘Literature reference(s)’:
N Engl J Med. 1997;336:309-15.
• No copy of the literature article required since the copy
was already submitted for case 1.
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VI. Appendix 3 Modalities for reporting
VI. Appendix 3.1 Interim arrangements
Figure VI.3. Business process map - Suspected adverse reaction reporting in EU – Interim
arrangements
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Table VI.3. Process description - Suspected adverse reaction reporting in EU - Interim arrangements
No. Step Description Responsible
Organisation
1 Start.
Receive report.
Marketing Authorisation Holder
(MAH) receives information on a
suspected adverse reaction from a
patient, healthcare professional or
other valid reporter. If the case has
been received from an EU NCA, do not
retransmit it to EudraVigilance (EV).
MAH
2 Open case. Open and create an individual case safety
report.
MAH
3 Is case from EEA? Did the adverse reactions occur in the EU?
If No, go to step 3.1.
If Yes, got so step 5.
MAH
3.1 Is case serious? If No, go to step 3.2.
If Yes, got to step 4.
MAH
3.2 End. The case is now stored in the MAHs
pharmacovigilance database. Normal
follow-up activities should continue
and if any follow-up is received,
return to step 1.
MAH
4 Send to EV & relevant NCAs. Transmit the serious case electronically,
in ICH E2B(R2) format as an xml message
within the 15-day time frame to EV and to
the relevant NCAs, where required. The
case goes to step 4.1 & step 6.
MAH
4.1 Receive in EV. Receive the message in EV database from
MAH or NCA.
EMA
4.2 Technical Validation (EV
Business Rules).
Every message that is received in EV is
validated against the EudraVigilance
Business Rules and an Acknowledgement
message (ACK) is created specifying
whether or not the message & the case(s)
therein are valid.
A valid message will have an ACK code
01. A non-valid message will have an ACK
code 02 (if a case contained therein is
non-valid) or 03 (if the message itself is
not correctly formatted).
EMA
4.3 Store in EV. Once the case has been validated, it is
stored in EV.
EMA
4.4 Send ACK. The acknowledgement message created in
step 4.2 is transmitted to the case
sender, no later than 2 business days
following receipt of the case.
Go to step 16 for MAHs receiving the ACK.
Go to step 20 for NCAs receiving the ACK.
EMA
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No. Step Description Responsible
Organisation
Go to step 4.5 for the EMA’s next step.
4.5 Was ACK code 01? If No, go to step 4.6.
If Yes, go to step 4.7.
EMA
4.6 Await corrected case. The sender should correct every case with
an error ACK and retransmit within the
regulatory reporting timelines. Periodically
the EMA should assess all cases with an
error ACK for which a corrected case has
not been transmitted and contact the
Qualified Person responsible for
Pharmacovigilance (QPPV) to inform of
these missing corrected cases. If a sender
fails to correct cases, then this
information should be incorporated into
data quality assessments and the
appropriate committees should be
informed.
Go back to step 4.1 upon receipt of the
corrected case.
EMA
4.7 End. The case is now stored in EV &,
following duplicate detection &
recoding will be available for signal
detection and data quality analyses.
EMA
5 Send to relevant NCA. Transmit the case (serious, and if
required non-serious) electronically, in
ICH E2B(R2) format as an xml message
within the relevant time frames (15 or 90
days, as applicable), to the relevant NCA
for the Member State where the reaction
occurred. If country of occurrence has not
been specified, then country of primary
source should normally be taken to be the
occurrence country.
MAH
6 Receive in
PharmacoVigilance (PhV)
database.
Receive the message from MAH in the
NCA’s PhV database.
NCA
7 Technical Validation (EV
Business Rules).
Every message that is received in the
NCA’s PhV database should be validated
against the EudraVigilance Business Rules
and an Acknowledgement message (ACK)
is created specifying whether or not the
message & the case(s) therein are valid.
A valid message will have an ACK code
01. A non-valid message will have an ACK
code 02 (if a case contained therein is
non-valid) or 03 (if the message itself is
NCA
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No. Step Description Responsible
Organisation
not correctly formatted).
8 Store in EV. Once the case has been validated, it is
stored in the NCA’s PhV database.
NCA
9 Send ACK. The acknowledgement message created in
step 7 is transmitted to the case sender
no later than 2 business days following
receipt of the case.
Go to step 16 for MAHs receiving the ACK.
Go to step 10 for the NCA’s next step.
NCA
10 Was ACK code 01? If No, go to step 10.1.
If Yes, go to step 11.
NCA
10.1 Await corrected case. The MAH should correct every case with
an error ACK and retransmit it within the
regulatory reporting timelines. Periodically
the NCA should assess all cases with an
error ACK for which a corrected case has
not been transmitted and contact the
QPPV to inform them of these missing
corrected cases. If a sender fails to
correct cases, then this information
should be incorporated into any data
quality assessments performed and the
appropriate action can be taken.
Go back to step 6 upon receipt of the
corrected case.
NCA
11 Was case from NCA’s MS? Did the case occur in the territory of the
receiving NCA?
If No, go to step 11.1.
If Yes, go to step 12.
NCA
11.1 End. The case is now stored in the NCA’s
pharmacovigilance database &,
following duplicate detection &
recoding will be available for signal
detection and data quality analyses.
NCA
12 Send to EV & MAH. Transmit the serious case electronically,
in ICH E2B(R2) format as an xml message
within the 15-day time frame to EV and to
the relevant MAH(s).
Go to step 4.1 for reception of the case in
EV
Go to step 24 for reception of the case by
the relevant MAH(s)
NCA
13 Start.
Receive report.
NCA receives information on a
suspected adverse reaction from a
patient, healthcare professional or
other valid reporter concerning a
NCA
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No. Step Description Responsible
Organisation
suspected adverse reaction occurring
in the territory of the receiving
competent authority.
14 Open case. Open and create an individual case safety
report.
NCA
15 Is case serious? If No, go to step 15.1
If Yes, go to step 12
NCA
15.1 End The case is now stored in the NCA’s
pharmacovigilance database &,
following duplicate detection &
recoding will be available for signal
detection and data quality analyses.
NCA
16 Receive ACK. Receive the ACK message, associate it
with the relevant case(s) and check to
ensure that the case was considered
valid.
MAH
17 Was ACK code 01? If yes, go to step 17.1.
If no, then the regulatory timeline clock
has not stopped and the case should be
corrected and re-transmitted to EV within
the relevant regulatory reporting
timelines. Day 0 remains as the day that
the first information was received. A 02 or
03 ACK does not constitute new
information. Go to step 18 (Correct case).
MAH
17.1 End. End the process of transmitting this
version of the case to EV or NCA.
Normal follow-up activities should
continue and if any follow-up is
received, return to step 1.
MAH
18 Correct case. Correct the case to remove the errors
identified in the ACK.
MAH
19 Retransmit to the organisation
which rejected the case.
Retransmit the corrected case to the
organisation which rejected the case with
ACK code 02 or 03.
Got to step 4.1 &/or step 6 as
appropriate.
MAH
20 Receive ACK. Receive the ACK message, associate it
with the relevant case(s) and check to
ensure that the case was considered
valid.
NCA
21 Was ACK code 01? If yes, go to step 23.
If no, then the regulatory timeline clock
has not stopped and the case should be
corrected and re-transmitted to EV within
the relevant regulatory reporting
NCA
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No. Step Description Responsible
Organisation
timelines. Day 0 remains as the day that
the first information was received. A 02 or
03 ACK does not constitute new
information. Go to step 22 (Correct case).
22 Correct case. Correct the case to remove the errors
identified in the ACK and retransmit the
case to EV and to the relevant MAH(s) (go
back to step 12).
NCA
23 End. End the process of transmitting this
version of the case to EV and to the
relevant MAH(s). Normal follow-up
activities should continue and if any
follow-up is received, return to step 6
or 13.
NCA
24 Receive report from NCA MAH receives information on a
suspected adverse reaction from an
NCA.
This case should not be retransmitted
to EV and to the NCA which
transmitted it to the MAH
MAH
25 End The case is now stored in the MAH’s
pharmacovigilance database &,
following duplicate detection &
recoding will be available for signal
detection and data quality analyses.
MAH
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VI. Appendix 3.1.1 Interim arrangements applicable to marketing
authorisation holders
Table VI.4. Reporting requirements applicable to marketing authorisation holders - Interim
arrangements
Marketing authorisation
procedure
Origin Adverse reaction type Destination Time
frame
• Centralised
• Mutual recognition,
decentralised or
subject to referral
• Purely national
EU All serious • Member State(1) where
suspected adverse
reaction occurred
15 days
All non-serious • Member State where
suspected adverse
reaction occurred, if
required (See Table
VI.5)
90 days
Non-
EU
All serious • EudraVigilance database
• Member States where
suspected medicinal
product is authorised, if
required (See Table
VI.5)
15 days
(1) Member States may request marketing authorisation holders to report those cases to EudraVigilance.
This will be further addressed in a specific question and answer document.
Table VI.5. Reporting requirements applicable to marketing authorisation holders – Interim
arrangements – Member States requirements
Marketing authorisation
procedure
Origin Adverse
reaction type
Destination YES NO
• Centralised
• Mutual recognition,
decentralised or
subject to referral
• Purely national
EU All non-serious Member State
where suspected
adverse reaction
occurred
AT,
DE1
DK,
IS, PL,
RO
BE, BG, CY, CZ,
DE, EE, ES, FI,
FR, GR, HU, IE,
IT, LI, LT, LU, LV,
MT, NL, NO, PT,
SE, SI, SK, UK
Non-
EU
All serious Member States
where suspected
medicinal
product is
authorised
DE,
SK,
UK
AT, BE, BG, CY,
CZ, DK, EE, ES,
FI, FR, GR, HU,
IE, IS, IT, LI, LT,
LU, LV, MT, NL,
NO, PL, PT, RO,
SE, SI
DE1: Only for non-serious cases related to vaccines reportable to the Paul-Ehrlich-Institut. Reporting of
other non-serious cases related to non-vaccines medicinal products will only be requested individually
in case of safety concerns.
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VI. Appendix 3.1.2 Interim arrangements applicable to competent
authorities in Member States
Table VI.6. Reporting requirements applicable to competent authorities in Member States - Interim
arrangements
Marketing authorisation
procedure
Origin Adverse reaction type Destination Time
frame
• Centralised
• Mutual recognition,
decentralised or
subject to referral
• Purely national
EU All serious • EudraVigilance database
• Marketing authorisation
holder of the suspected
medicinal product
15 days
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VI. Appendix 3.2 Final arrangements
Figure VI.4. Business process map - Suspected adverse reaction reporting in EU - Final arrangements
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Table VI.7. Process description - Suspected adverse reaction reporting in EU - Final arrangements
No. Step Description Responsible
Organisation
1 Start.
Receive report.
National Competent Authority (NCA)
or Marketing Authorisation Holder
(MAH) receives information on a
suspected adverse reaction from a
patient, healthcare professional or
other valid reporter.
If the case has been received from an
EU NCA, do not retransmit it to
EudraVigilance (EV).
MAH/NCA
2 Open case. Open and create an individual case safety
report.
MAH/NCA
3 Is case serious? If No go to step 3.1.
If Yes, go to step 4.
3.1 Is case from EEA? If No go to step 11.1.
If Yes, go to step 4.
4 Send to EV. Transmit the case (all serious and EU
non-serious) electronically, in ICH
E2B(R2) format as an xml message within
the relevant time frame (15 or 90 days,
as applicable), to EV.
MAH/NCA
5 Receive in EV. Receive the message in the EV. EMA
6 Technical Validation (EV
Business Rules).
Every message that is received in EV is
validated against the EudraVigilance
Business Rules and an Acknowledgement
message (ACK) is created specifying
whether or not the message & the case(s)
therein are valid.
A valid message will have an ACK code
01. A non-valid message will have an ACK
code 02 (if a case contained therein is
non-valid) or 03 (if the message itself is
not correctly formatted).
EMA
7 Store in EV. Once the case has been validated, it is
stored in the EV.
EMA
8 Send ACK. The acknowledgement message created in
step 6 is transmitted to the case sender
no later than 2 business days following
receipt of the case.
Go to step 9 for the EMA’s next step.
Go to step 10 for MAH/NCA’s next step.
EMA
9 Was ACK code 01? If No go to step 9.1.
If Yes, go to step 9.2.
EMA
9.1 Await corrected case. The sender should correct every case with
an error ACK and retransmit it within the
EMA
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No. Step Description Responsible
Organisation
regulatory reporting timelines. Periodically
the EMA should assess all cases with an
error ACK for which a corrected case has
not been transmitted and contact the
Qualified Person responsible for
PharmacoVigilance (QPPV) to inform these
missing corrected cases. If a sender fails
to correct cases, this information should
be incorporated into data quality
assessments and the appropriate
committees should be informed.
Go back to step 5 upon receipt of the
corrected case.
9.2 End. The case is now stored in EV &,
following duplicate detection &
recoding will be available for signal
detection and data quality analyses.
If the case occurred in the EU and
was transmitted to EV by a MAH, it
will be rerouted to the relevant NCA
(see VI. Appendix 3.3)
EMA
10 Receive ACK. Receive the ACK message, associate it
with the relevant case(s) and check to
ensure that the case was considered
valid.
MAH/NCA
11 Was ACK code 01? If yes, go to step 11.1.
If no, then the regulatory timeline clock
has not stopped and the case should be
corrected and re-transmitted to EV within
the relevant regulatory reporting
timelines. Day 0 remains as the day that
the first information was received. A 02 or
03 ACK does not constitute new
information. Go to step 12 (Correct case)
MAH/NCA
11.1 End. End the process for this version of the
case. Normal follow-up activities
should continue and if any follow-up
is received, return to step 1.
MAH/NCA
12 Correct case. Correct the case to remove the errors
identified in the ACK and retransmit the
case to EV (go back to step 4).
MAH/NCA
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VI. Appendix 3.2.1 Final arrangements applicable to marketing
authorisation holders
Table VI.8. Reporting requirements applicable to marketing authorisation holders - Final
arrangements
Marketing
authorisation
procedure
Origin Adverse reaction
type
Destination Time
frame
• Centralised
• Mutual recognition,
decentralised or
subject to referral
• Purely national
EU All serious • EudraVigilance database 15 days
All non-serious • EudraVigilance database 90 days
Non-
EU
All serious • EudraVigilance database 15 days
VI. Appendix 3.2.2 Final arrangements applicable to competent authorities
in Member States
Table VI.9. Reporting requirements applicable to competent authorities in Member States - Final
arrangements
Marketing
authorisation
procedure
Origin Adverse reaction
type
Destination Time
frame
• Centralised
• Mutual recognition,
decentralised or
subject to referral
• Purely national
EU All serious • EudraVigilance database 15 days
All non-serious • EudraVigilance database 90 days
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VI. Appendix 3.3 Transmission and rerouting of ICSRs to competent
authorities in Member States 42
Figure VI.5. Business process map - Transmission and rerouting of ICSRs to competent authorities in
Member States
42 Once the functionalities of the EudraVigilance database specified in [REG Art 24(2)] are established.
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Table VI.10. Process description - Transmission and rerouting of ICSRs to competent authorities in
Member States 43
No. Name Description Responsible
Organisation
1 Start.
Receive report.
Marketing Authorisation Holder
(MAH) receives information on a
suspected adverse reaction from a
patient, healthcare professional or
other valid reporter.
MAH
2 Open case. Open and create an individual case safety
report.
MAH
3 Send to EudraVigilance (EV). Transmit the case electronically, in ICH
E2B(R2) format as an xml message within
the relevant time frames (15 or 90 days,
as applicable), to EV.
MAH
4 Receive in EV. Receive the message in the EV. EMA
5 Technical Validation (EV
Business Rules).
Every message that is received in EV is
validated against the EudraVigilance
Business Rules and an Acknowledgement
message (ACK) is created specifying
whether or not the message & the case(s)
therein are valid.
A valid message will have an ACK code
01. A non-valid message will have an ACK
code 02 (if a case contained therein is
non-valid) or 03 (if the message itself is
not correctly formatted).
EMA
6 Store in EV. Once the case has been validated, it is
stored in EV.
EMA
7 Send ACK. The acknowledgement message created in
step 5 is transmitted to the case sender
no later than 2 business days following
receipt of the case.
EMA
7.1 Receive ACK. Receive the ACK message, associate it
with the relevant case(s) and check to
ensure that the case was considered
valid.
MAH
7.2 Was ACK code 01? If Yes, go to step 7.2.1.
If no, then the regulatory timeline clock
has not stopped and the case should be
corrected and re-transmitted to EV within
the relevant regulatory reporting
timelines. Day 0 remains as the day that
the first information was received. A 02 or
03 ACK does not constitute new
information. Go to step 7.2.2 (Correct
MAH
43 Once the functionalities of the EudraVigilance database specified in [REG Art 24(2)] are established.
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No. Name Description Responsible
Organisation
case).
7.2.1 End. End the process of transmitting this
version of the case to EV. Normal
follow-up activities should continue
and if any follow-up is received,
return to step 1.
MAH
7.2.2 Correct case. Correct the case to remove the errors
identified in the ACK and retransmit the
case to EV (go back to step 3).
MAH
8 Was ACK code 01? If yes, go to step 9.
If no, perform no further processing on
this version of the case and go to step 8.1
EMA
8.1 Await corrected case. The sender should correct every case with
an error ACK and retransmit it within the
regulatory reporting timelines. Periodically
the EMA should assess all cases with an
error ACK for which a corrected case has
not been transmitted and contact the
Qualified Person responsible for
PharmacoVigilance (QPPV) to inform of
these missing corrected cases. If a sender
fails to correct cases, his information
should be incorporated into data quality
assessments and the appropriate
committees should be informed.
EMA
9 Assess cases in message. Whenever a message has passed the
technical validation, the cases therein
should be immediately assessed to
determine the country where the reaction
occurred for regulatory reporting
purposes.
EMA
10 Was case from EU? For every case, assess whether the
country of occurrence is in the EU.
If Yes, go to step 11.
If No, go to step 10.1
EMA
10.1 End. The case is now stored in EV &,
following duplicate detection &
recoding will be available for signal
detection and data quality analyses.
EMA
11 Extract cases from message. The cases occurring in the EU will be
extracted from the message for
processing prior to retransmission.
EMA
12 Technical Validation. Message sender identifier (ICH M2 M.1.5)
of reporting MAH is inserted in Sender
organisation field (ICH-E2B(R2) A.3.1.2)
prior to retransmission. This is to permit
EMA
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No. Name Description Responsible
Organisation
the receiving National Competent
Authority (NCA) to unambiguously identify
the MAH responsible for transmitting the
case to EV.
13 Send to relevant NCA The case is transmitted to the relevant
NCA of the Member State where the
reaction occurred with no other changes.
Where a Member State has more than
one NCA responsible for post-marketing
reports, the cases occurring in that
Member State are sent to all relevant
NCAs.
EMA
14 Receive in
PharmacoVigilance (PhV)
database.
The relevant NCA receives the message in
its pharmacovigilance database
NCA
15 Technical Validation (EV
Business Rules).
Every message should be validated
against the EudraVigilance Business Rules
(the same business rules as in Step 5 and
an Acknowledgement message (ACK) is
created specifying whether or not the
message & the case(s) therein are valid.
A valid message will have an ACK code
01. A non-valid message will have an ACK
code 02 (if a case contained therein is
non-valid) or 03 (if the message itself is
not correctly formatted).
NCA
16 Store in PhV database. Once the case has been validated, it is
stored in the pharmacovigilance database.
NCA
17 Send ACK. The acknowledgement message created in
step 15 is transmitted to EV no later than
2 business days following receipt of the
case.
NCA
17.1 End The case is now stored in the NCA’s
pharmacovigilance database &,
following duplicate detection &
recoding will be available for signal
detection and data quality analyses.
NCA
18 Receive ACK The acknowledgement message sent in
step 17 is received & stored in EV.
EMA
19 End The case has now been successfully
retransmitted to the relevant NCA.
EMA
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VI. Appendix 4 Transmission of ICSRs to World Health
Organisation (WHO)44
Figure VI.6. Business process map - Transmission of ICSRs to World Health Organisation (WHO)
Collaborating Centre
44 Once the functionalities of the EudraVigilance database specified in [REG Art 24(2)] are established.
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Table VI.11. Process description - Transmission of ICSRs to World Health Organisation (WHO)
Collaborating Centre 45
No. Step Description Responsible
Organisation
1 Start.
Receive report.
National Competent Authority (NCA)
or Marketing Authorisation Holder
(MAH) receives information on a
suspected adverse reaction from a
patient, healthcare professional or
other valid reporter.
MAH/NCA
2 Open case. Open and create an individual case safety
report.
MAH/NCA
3 Send to EV. Transmit the case electronically, in ICH
E2B(R2) format as an xml message within
the relevant time frames (15 or 90 days,
as applicable), to EudraVigilance (EV).
MAH/NCA
4 Receive in EV. Receive the message in EV. EMA
5 Technical Validation (EV
Business Rules).
Every message that is received in EV is
validated against the EudraVigilance
Business Rules and an Acknowledgement
message (ACK) is created specifying
whether or not the message & the case(s)
therein are valid.
A valid message will have an ACK code
01. A non-valid message will have an ACK
code 02 (if a case contained therein is
non-valid) or 03 (if the message itself is
not correctly formatted).
EMA
6 Store in EV. Once the case has been validated, it is
stored in EV.
EMA
7 Send ACK. The acknowledgement message created in
step 5 is transmitted to the case sender
no later than 2 business days following
receipt of the case.
EMA
7.1 Receive ACK. Receive the ACK message, associate it
with the relevant case(s) and check to
ensure that the case was considered valid.
MAH/NCA
7.2 Was ACK code 01? If Yes, go to step 7.2.1.
If no, then the regulatory timeline clock
has not stopped and the case should be
corrected and re-transmitted to EV within
the relevant regulatory reporting
timelines. Day 0 remains as the day that
the first information was received. A 02 or
03 ACK does not constitute new
information. Go to step 7.2.2 (Correct
MAH/NCA
45 Once the functionalities of the EudraVigilance database specified in [REG Art 24(2)] are established.
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No. Step Description Responsible
Organisation
case).
7.2.1 End End the process of transmitting this
version of the case to EV. Normal
follow-up activities should continue
and if any follow-up is received,
return to step 1.
MAH/NCA
7.2.2 Correct case Correct the case to remove the errors
identified in the ACK and retransmit the
case to EV (go back to step 3).
MAH/NCA
8 Was ACK code 01? If yes, go to step 9
If no, perform no further processing on
this version of the case and go to step 8.1
EMA
8.1 Await corrected case. The sender should correct every case with
an error ACK and retransmit within the
regulatory reporting timelines. Periodically
the EMA should assess all cases with an
error ACK for which a corrected case has
not been transmitted and contact the
Qualified Person responsible for
PharmacoVigilance (QPPV) to inform of
these missing corrected cases. If a sender
fails to correct cases, this information
should be incorporated into data quality
assessments and the appropriate
committees should be informed.
EMA
9 Assess cases in message. Once a week, for every message that has
passed the technical validation, the cases
therein should be assessed to determine
the country where the reaction occurred
for regulatory reporting purposes.
EMA
10 Was case from EU? For every case, assess whether the
country of occurrence is in the EU.
If Yes, go to step 11.
If No, go to step 10.1.
EMA
10.1 End. The case is now stored in EV &,
following duplicate detection &
recoding will be available for signal
detection and data quality analyses.
EMA
11 Extract cases from message The cases occurring in the EU is extracted
from the message for processing prior to
retransmission.
EMA
12 Redact & replace data in line
with EV Data Access policy.
Prior to sending the cases to the World
Health Organisation (WHO) Collaborating
Centre, the extracted copies of the cases
have some data elements redacted and
replaced in line with the EV Data Access
EMA
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No. Step Description Responsible
Organisation
Policy in order to ensure personal data
protection.
13 Copy cases to physical media. The cases are copied to physical media. EMA
14 Send to WHO. The physical media is sent to WHO
Collaborating Centre.
EMA
15 Receive physical media WHO Collaborating Centre receives
the physical media.
WHO
16 Store cases in
pharmacoVigilance (PhV)
database.
Once the cases have been validated, they
are stored in the pharmacovigilance
database.
WHO
17 End. Cases are stored in the WHO
Collaborating Centre’s
pharmacovigilance database &,
following duplicate detection &
recoding will be available for signal
detection and data quality analyses.
WHO
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VI. Appendix 5 Nullification of cases
General principles regarding the nullification of cases are provided in VI.C.6.2.2.10. The following
recommendations should also be applied:
• The value in the data element ‘Report nullification’ (ICH-E2B(R2) A.1.13) should be set to ‘Yes’ and
the nullification reason should be provided in the data element ‘Reason for nullification’ (ICH-
EB(R2) A.1.13.1). The nullification reason should be clear and concise to explain why this case is
no longer considered to be a valid report. For example a nullification reason stating, ‘the report no
longer meets the reporting criteria’ or ‘report sent previously in error’ are not detailed enough
explanations.
• An individual case can only be nullified by the sending organisation.
• Once an individual case has been nullified, the case cannot be reactivated.
• If it becomes necessary to resubmit the case that has been previously nullified, a new ‘Sender’s
(case) safety report unique identifier’ (ICH-E2B(R2) A.1.0.1) and ‘Worldwide unique case
identification number’ (ICH-E2B(R2) A.1.10) should be assigned.
• Individual versions (i.e. follow-up reports) of a case cannot be nullified, only the entire individual
case to which they refer.
Table VI.12. Examples of scenarios for which ICSRs should be nullified
Ex. Scenario Action
1 An individual case has been identified as
a duplicate of another individual case
previously submitted.
One of the individual cases should be nullified. The
remaining valid case should be updated with any
additional relevant information from the nullified
case.
2 A wrong ‘Worldwide unique case
identification number’ (ICH-E2B(R2)
A.1.10) was accidentally used and does
not refer to an existing case.
The case with the wrong ‘Worldwide unique case
identification number’ (ICH-E2B(R2) A.1.10) should
be nullified.
A new case should be created with a correct
‘Worldwide unique case identification number’.
3 On receipt of further information it is
confirmed that that the adverse reaction
occurred before the suspect drug(s) was
taken.
The case should be nullified.
4 On receipt of further information on an
individual case, it is confirmed that the
patient did not receive the suspect drug.
Minimum reporting criteria for an ICSR
as outlined in VI.B.2 are no longer met.
The case should be nullified.
5 On receipt of further information it is
confirmed by the same reporter that the
reported adverse reaction(s) did not
occur to the patient. Minimum reporting
The case should be nullified.
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Ex. Scenario Action
criteria for an ICSR as outlined in
VI.B.2are no longer met.
6 On receipt of further information it is
confirmed that there was no valid patient
for the individual case. Minimum
reporting criteria for an ICSR as outlined
in VI.B.2 are no longer met.
If it is not possible to obtain confirmation of the
patient’s existence, then the case should be nullified.
• Individual cases that have been nullified should not be used for scientific evaluation, however, they
should remain in the database for auditing purposes.
• In addition, in case of duplicate reports where one report needs to be nullified, the update of the
remaining case should be performed in the form of a follow-up report46. Information on the
identification of the nullified case(s) should be provided in the data element ‘Source(s) of the case
identifier (e.g. name of the company, name of regulatory agency)’ (ICH-E2B(R2) A.1.11.1 ) and in
the data element ‘Case identifier(s)’ (ICH-E2B(R2) A.1.11.2).
Table VI.13. Examples of scenarios for which ICSRs should NOT be nullified
Ex. Scenario Action
7 A wrong ‘Worldwide unique case
identification number’ (ICH E2B(R2)
A.1.10) was accidentally used. This
wrong ICH-E2B(R2) A.1.10 ‘Worldwide
unique case identification number’
referred to an existing case.
The report with the wrong ‘Worldwide unique case
identification number’ (ICH-E2B(R2) A.1.10) should
not be nullified.
A follow-up report should be submitted to correct
the information previously submitted.
A new ICSR should be created and submitted with
the correct ‘Worldwide unique case identification
number’.
8 On receipt of further information on an
individual case, it is confirmed that the
patient did not receive the marketing
authorisation holder’s suspect drug.
However, the patient received other
suspect drugs and the minimum
reporting criteria for an ICSR are still
met.
The case should not be nullified.
9 On receipt of further information the
reporter has confirmed that the reported
adverse reaction is no longer considered
to be related to the suspect medicinal
product(s).
The case should not be nullified.
A follow-up report should be submitted within the
appropriate time frame with the updated information
on the case.
46 As presented in the Guideline on the Detection and Management of Duplicate Individual Cases and Individual Case Safety
Reports (ICSRs), EMA/13432/2009.
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/06/WC500129037.pdf
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Ex. Scenario Action
10 Change of the individual case from
serious to non-serious (downgrading).
The case should not be nullified.
A follow-up report should be submitted with the data
element ‘Seriousness’ (ICH-E2B(R2) A.1.5.1)
populated with the value ‘No’ without selection of a
value for the data element ‘Seriousness criteria’
(ICH-E2B(R2) A.1.5.2).
The data element ‘Does this case fulfil the local
criteria for an expedited report?’ (ICH-E2B(R2) field
A.1.9) should remain populated with the value ‘Yes’.
11 The primary source country has
changed, which has an impact on the
ICH-E2B(R2) convention regarding the
creation of the ‘Worldwide unique case
identification number’ (ICH-E2B(R2)
A.1.10).
The case should not be nullified.
The ‘Sender’s (case) safety report unique identifier’
(ICH-E2B(R2) A.1.0.1) can be updated on the basis
of the new primary source country code. However,
the ‘Worldwide unique case identification number’
(ICH-E2B(R2) A.1.10) should remain unchanged.
If, for some technical reason, the sender’s local
system is not fully ICH-E2B(R2) compliant and
cannot follow this policy, then the sender should
nullify the original case. A new case should be
created with a new ‘Worldwide unique case
identification number’ (ICH-E2B(R2) A.1.10)
reflecting the changed primary source country code.
The ‘Worldwide unique case identification number’
(ICH-E2B(R2) A.1.10) of the case that was nullified
should be reflected in the data elements ‘Other case
identifiers in previous transmissions’ (ICH-E2B(R2)
A.1.11).
12 The suspected medicinal product belongs
to another marketing authorisation
holder (e.g. a product with the same
active substance but marketed under a
different invented name).
The case should not be nullified.
It is recommended that the initial sender informs the
other marketing authorisation holder about this case
(including the ‘Worldwide unique case identification
number’ (ICH-E2B(R2) A.1.10) used). The original
organisation should also submit a follow-up report to
provide this new information.
The other concerned marketing authorisation holder
should create a new case and specify the reference
case number and the name of the initial sending
marketing authorisation holder in the data elements
‘Source(s) of the case identifier (e.g. name of the
company name of regulatory agency)’ (ICH-E2B(R2)
A.1.11.1) and ‘Case identifier(s)’ (ICH-E2B(R2)
A.1.11.2). This will allow grouping the cases in the
EudraVigilance database.
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Ex. Scenario Action
13 The suspected medicinal product taken
does not belong to the marketing
authorisation holder (same active
substance, the invented name is
unknown and the report originates from
a country, where the marketing
authorisation holder has no marketing
authorisation for the medicinal product in
question).
The case should not be nullified.
The marketing authorisation holder should submit a
follow-up report with this information within the
appropriate time frame.
14 The case is mistakenly reported by the
marketing authorisation holder A
although the marketing authorisation
holder B as co-marketer is responsible
for reporting the case.
The case should not be nullified.
An explanation should be sent by the marketing
authorisation holder A to the co-marketer marketing
authorisation holder B that the case has already
been reported. The marketing authorisation holder B
should provide any additional information on the
case as a follow-up report with the same ‘Worldwide
unique case identification number’ (ICH-E2B(R2)
A.1.10).
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VI. Appendix 6 Data quality monitoring of ICSRs transmitted
electronically
Figure VI.7. Business process map - Data quality monitoring of ICSRs transmitted electronically
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Table VI.14. Process description - Data quality monitoring of ICSRs transmitted electronically
The business map and process description describe a system where there is a separation between a
PharmacoVigilance DataBase (PhV DB) holder, the PhV DB holder’s data Quality Assessors (QA) and
the PhV DB holder’s auditors; however this is not mandatory and these functions may be performed by
the same people or groups.
No. Step Description Responsible
Organisation
1 Start.
Decide upon Sender to
evaluate.
Select one of the organisations that
has transmitted ICSRs to your
database.
Inputs into this decision can include,
but need not be limited to findings
from previous assessments and
requests from pharmacovigilance
audits.
PhV DB
holder
2 Sample ICSRs from Sender. Take a sample of ICSRs that were
transmitted by the selected sender
QA
3 Check for data quality errors. Check the cases for data quality errors.
The cases should be assessed against
appropriate published standards and
similar documents, for example the
MedDRA Term Selection Points to
Consider document.
QA
4 Write report and send to PhV
DB holder.
The findings from the data quality
assessment should be collated into a
single report. These can include related
checks, such as 15-day reporting
compliance, whether error reports are
corrected and similar statistical
information.
QA
5 Errors found? Were any errors found during the analysis
of the cases?
If No, go to step 5.1.
If Yes go to steps 5.2, 5.3 & 6.
PhV DB
holder
5.1 End. If there were no errors found, then
no further action needs to be taken.
The process can end until the next
time the sender is assessed.
The pharmacovigilance database
(PhV DB) holder may choose to share
this information with the assessed
sender and their auditors who may
wish to factor this in to
determinations of which sender to
assess.
PhV DB
holder
5.2 Highlight for PhV audit. If the PhV DB holder’s organisation has an
audit department, any significant findings
PhV DB holder
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No. Step Description Responsible
Organisation
should always be shared with them.
5.2.1 Prioritise for Audit. The audit or inspections department
should use the information provided to
them to feed into decisions about
prioritising organisations for audit or
inspection.
PhV DB
holder’s
auditors
5.3 INPUT: Findings from
previous assessments.
Any errors found (or even lack thereof)
should be incorporated into decisions
about which senders to evaluate & should
also inform the performance of the
assessments (e.g. targeting particular
types of case) and the report
(documenting whether previously
identified issues have been addressed).
PhV DB
holder
6 Inform sender of findings. Inform the sender of the findings,
including requested remedial actions (e.g.
retransmitting certain cases) and time
frames for those actions
PhV DB holder
7 Request meeting? The sender should have the option to
choose to request a meeting to discuss
the findings and appropriate remedial
action and time frames.
If no meeting is requested, go to step 7.1.
If a meeting is requested go to step 8.
Sender
7.1 Address the findings &
retransmit any required cases.
Address all findings, take necessary steps
to prevent recurrence of such findings &
retransmit any required cases.
Sender
7.2 End. Once all findings have been
addressed, the necessary steps taken
to prevent recurrence of such
findings and any required cases have
been retransmitted, the process can
end until the next time the sender is
assessed.
Sender
8 Have meeting. Upon request from one party, a meeting
should be held to discuss the findings of
quality assessments and appropriate
remedial and preventive actions to ensure
that the cases in the database are correct
and shall be so in the future.
PhV DB
holder &
Sender
9 End. Unless further action has been
specified (e.g. future meetings or
assessments), the process can end
until the next time the sender is
assessed.
PhV DB
holder
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VI. Appendix 7 Duplicate detection and management of ICSRs
Figure VI.8. Business process map - Duplicate detection and management of ICSRs
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Table VI.15. Process description - Duplicate detection and management of ICSRs
No. Step Description Responsible
organisation
1 Start.
Potential duplicate
detected.
Potential duplicates have been
detected by the PharmacoVigilance
Database (PhV DB) holder
organisation or the PhV DB holder
organisation is notified of potential
duplicates by a receiver of the cases.
PhV DB
holder
2 Assessment. All potential duplicates need
assessment by the organisation
Duplicate Management Team (DMT)
to confirm or deny their duplicate
status.
Following assessment there are 4 possible
outcomes:
• Not a Duplicate (go to step 2.1),
• More Information Needed (go to
step 2.2),
• Duplicates From Different Sender
(go to step 2.3),
• Duplicates From Same Sender (go
to step 2.4).
The outcome of all assessments should be
recorded to avoid continually reassessing
the same cases when further versions
arrive. These recorded outcomes can also
be used to refine the duplicate detection
methods during future development.
DMT
2.1 Not a Duplicate: Mark as
not a duplicate.
If the cases are assessed as not being
duplicates of one another, then mark both
cases as such.
Go to step 3 (End).
DMT
2.2 More information needed:
Log in tracking tool.
There should be some form of tool for
tracking when more information is
needed, when correspondence has been
sent, whether an answer was received
and, if so, when.
DMT
2.2.1 Write to Sender. More information is required in order to
be able to make a definite assessment.
The sender (who transmitted the case(s)
in question to the PhVDB holder’s
organisation) should be contacted to
request specific information necessary to
confirm or deny duplication.
Personal data protection must remain
paramount, so unsecured communications
should not include sufficient data to
PhV DB
holder
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No. Step Description Responsible
organisation
identify an individual.
2.2.2 Receive request, draft
and send response.
Once a request for more information has
been received, the Sender of the case
should respond promptly, either as a
follow-up version of the case or by
responding to the requester.
The DMT should then reassess the case
based on the new information (Go back to
step 2).
Sender
2.3 Duplicates Different
Senders: Create or
nominate master.
Once cases have been determined to be
duplicates of one another and have been
transmitted to the PhV DB holder by
different senders or reporters, then they
should be merged under a master case,
following the process described in chapter
2.3 “Management of duplicate cases” of
the Guideline on the Detection and
Management of Duplicate Individual Cases
and Individual Case Safety Reports
(ICSRs), EMA/13432/2009.
DMT
2.3.1 Deal with follow-ups. If any follow-ups arrive for any of the
cases, this information may require a
reassessment of the master case.
Reassess and, if necessary, amend the
master case as with any received follow-
up information.
Go to step 3 (End).
DMT
2.4 Duplicates Same Sender:
Log in tracking tool.
Once cases have been determined to be
duplicates of one another, and have been
transmitted to the PhV DB holder by the
same sender, then this decision and the
correspondence referred to in step 2.4.1
should be logged in the tracking tool
referred to in step 2.2.
DMT
2.4.1 Write to Sender. The sender organisation, as the source of
the duplicates, should be contacted in
accordance with chapter 2.3.3 of the
Guideline on the Detection and
Management of Duplicate Individual Cases
and Individual Case Safety Reports
(ICSRs), EMA/13432/2009.
The sender should be asked to confirm or
deny duplication and take appropriate
steps in accordance with chapter 2.3.1 of
the aforementioned Guideline.
PhV DB
holder
2.4.2 Receive request. Receive and log the communication Sender
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/06/WC500129037.pdf
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/06/WC500129037.pdf
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No. Step Description Responsible
organisation
containing information on suspected
duplicates in the Sender’s PhV DB.
2.4.3 Is it a duplicate? Assess the potential duplicates. Are the
cases duplicates of one another?
If Yes, go to step 2.4.3.1.
If No, go to step 2.4.3.2.
Sender
2.4.3.1 Merge duplicates. Merge the duplicates, taking into account
Flowchart 1 of chapter 2.3.1.3 of the
Guideline on the Detection and
Management of Duplicate Individual Cases
and Individual Case Safety Reports
(ICSRs), EMA/13432/2009.
Sender
2.4.3.1.1 Send follow-up/nullification. For the cases that are merged under the
master, send a nullification message to
the PhV DB holder.
For the case that is master, send the
updated case to the PhV DB holder as
follow-up information. The merging &
transmission should be completed
promptly and in any case within 15 days
of the date of receipt of the information
from the PhV DB holder that the cases
were considered to be possible duplicates.
This date should be treated as the date of
receipt of most recent information for
regulatory reporting purposes.
Sender
2.4.3.1.2 End. The duplicates have now been
removed from both the Sender’s
system and that of the PhV DB holder
and only the master should be
available for signal detection and
data quality analyses.
Unless follow-up information is
received, then no further steps need
be taken.
Sender
2.4.3.2 Draft and send a response. Reply to the PhV DB holder who sent the
communication informing that the cases
are not duplicates.
Sender
2.4.3.2.1 Mark as “Not a
duplicate”.
Upon receipt of confirmation from the
Sender organisation that the cases are
not duplicates, mark the cases as “Not a
duplicate” & go to step 3 (End).
DMT
3 End. No further action is required for this
couple.
DMT
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/06/WC500129037.pdf
VI.A. Introduction
VI.A.1. Scope
VI.A.2. Definitions
VI.A.2.1. Adverse reaction
VI.A.2.1.1. Causality
VI.A.2.1.2. Overdose, off-label use, misuse, abuse, occupational exposure
VI.A.2.2. Medicinal product
VI.A.2.3. Primary source
VI.A.2.4 Seriousness
VI.A.2.5. Individual Case Safety Report (ICSR)
VI.B. Structures and Processes
VI.B.1. Collection of reports
VI.B.1.1. Unsolicited reports
VI.B.1.1.1. Spontaneous reports
VI.B.1.1.2. Literature reports
VI.B.1.1.3. Reports from other sources
VI.B.1.1.4. Information on suspected adverse reactions from the internet or digital media
VI.B.1.2. Solicited reports
VI.B.2. Validation of reports
VI.B.3. Follow-up of reports
VI.B.4. Data management
VI.B.5. Quality management
VI.B.6. Special situations
VI.B.6.1. Use of a medicinal product during pregnancy or breastfeeding
VI.B.6.2. Use of a medicinal product in a paediatric or elderly population
VI.B.6.3. Reports of overdose, abuse, off-label use, misuse, medication error or occupational exposure
VI.B.6.4. Lack of therapeutic efficacy
VI.B.7. Reporting of ICSRs
VI.B.7.1. Reporting time frames
VI.B.8. Reporting modalities
VI.C. Operation of the EU Network
VI.C.1. Interface with safety reporting rules for clinical trials and post authorisation studies in the EU
VI.C.1.1. Interface with clinical trials
VI.C.1.2. Interface with post-authorisation studies
VI.C.1.2.1. Non-interventional studies
VI.C.1.2.2. Compassionate use, named patient use
VI.C.2. Collection of reports
VI.C.2.1. Member States responsibilities
VI.C.2.2. Marketing authorisation holders responsibilities
VI.C.2.2.1. Spontaneous reports
VI.C.2.2.2. Solicited reports
VI.C.2.2.3. Case reports published in the scientific and medical literature
VI.C.2.2.4. Suspected adverse reactions related to quality defect or falsified medicinal products
VI.C.2.2.5. Suspected transmission via a medicinal product of an infectious agent
VI.C.2.2.6. Emerging safety issues
VI.C.2.2.7. Period between the submission of the marketing authorisation application and the granting of the marketing authorisation
VI.C.2.2.8. Period after suspension, revocation or withdrawal of marketing authorisation
VI.C.2.2.9. Period during a public health emergency
VI.C.2.2.10. Reports from class action lawsuits
VI.C.2.2.11. Reports from patient support programmes and market research programmes
VI.C.3. Reporting time frames
VI.C.4. Reporting modalities
VI.C.4.1. Interim arrangements
VI.C.4.2. Final arrangements
VI.C.5. Collaboration with the World Health Organization and the European Monitoring Centre for Drugs and Drug Addiction
VI.C.6. Electronic exchange of safety information in the EU
VI.C.6.1. Applicable guidelines, definitions, international formats, standards and terminologies
VI.C.6.2. Electronic Reporting of Individual Case Safety Reports
VI.C.6.2.1. EudraVigilance Database Modules
VI.C.6.2.1.1. Adverse reaction data collected in the EudraVigilance Post-Authorisation Module
VI.C.6.2.1.2. Adverse Reaction Data Collected in the EudraVigilance Clinical Trial Module
VI.C.6.2.2. Preparation of Individual Case Safety Reports
VI.C.6.2.2.1. General principles
VI.C.6.2.2.2. Information on suspect, interacting and concomitant medicinal products
VI.C.6.2.2.3. Suspected adverse reactions
VI.C.6.2.2.4. Case narrative, causality assessment and comments
VI.C.6.2.2.5. Test results
VI.C.6.2.2.6. Supplementary information
VI.C.6.2.2.7. Follow-up information
VI.C.6.2.2.8. What to take into account for data privacy laws
VI.C.6.2.2.9. Handling of languages
VI.C.6.2.2.10. Nullification of cases
VI.C.6.2.3. Special situations
VI.C.6.2.3.1. Use of a medicinal product during pregnancy or breastfeeding
VI.C.6.2.3.2. Suspected adverse reaction reports published in the scientific and medical literature
VI.C.6.2.3.3. Suspected adverse reactions related to overdose, abuse, off-label use, misuse, medication error or occupational exposure
VI.C.6.2.3.4. Lack of therapeutic efficacy
VI.C.6.2.3.5. Suspected adverse reactions related to quality defect or falsified medicinal products
VI.C.6.2.3.6. Suspected transmission via a medicinal product of an infectious agent
VI.C.6.2.3.7. Reports originating from organised data collection systems and other systems
VI.C.6.2.3.8. Receipt of missing minimum information
VI.C.6.2.4. Data quality of individual case safety reports transmitted electronically and duplicate management
VI.C.6.2.5. Electronic re-transmission of ICSRs between multiple senders and receivers
VI.C.6.2.6. Electronic reporting through company’s headquarters
VI.C.6.3. Electronic submission of information on medicinal products
VI. Appendix 1 Identification of biological medicinal products40F
VI. Appendix 2 Detailed guidance on the monitoring of scientific and medical literature
VI. App2.1 When to start and stop searching in the scientific and medical literature
VI. App2.2 Where to look
VI. App2.3 Database Searches
VI. App2.3.1 Precision and recall
VI. App2.3.2 Search construction
VI. App2.3.3 Selection of product terms
VI. App2.3.4 Selection of search terms
VI. App2.3.5 Limits to a search
VI. App2.4 Record keeping
VI. App2.5 Outputs
VI. App2.6 Review and selection of articles
VI. App2.7 Day zero
VI. App2.8 Duplicates
VI. App2.9 Contracting out Literature Search Services
VI. App2.10 Electronic submission of copies of articles published in the scientific and medical literature
VI. Appendix 3 Modalities for reporting
VI. Appendix 3.1 Interim arrangements
VI. Appendix 3.1.1 Interim arrangements applicable to marketing authorisation holders
VI. Appendix 3.1.2 Interim arrangements applicable to competent authorities in Member States
VI. Appendix 3.2 Final arrangements
VI. Appendix 3.2.1 Final arrangements applicable to marketing authorisation holders
VI. Appendix 3.2.2 Final arrangements applicable to competent authorities in Member States
VI. Appendix 3.3 Transmission and rerouting of ICSRs to competent authorities in Member States 41F
VI. Appendix 4 Transmission of ICSRs to World Health Organisation (WHO)43F
VI. Appendix 5 Nullification of cases
VI. Appendix 6 Data quality monitoring of ICSRs transmitted electronically
VI. Appendix 7 Duplicate detection and management of ICSRs
29.07.2014
Datei
PD
9 December 2013
EMA/816292/2011 Rev 1*
Guideline on good pharmacovigilance practices (GVP)
Module VII – Periodic safety update report (Rev 1)
Date for coming into effect of first version 2 July 2012
Draft Revision 1* finalised by the Agency in collaboration with Member
States
21 March 2013
Draft Revision 1 agreed by ERMS FG 27 March 2013
Draft Revision 1 adopted by Executive Director 19 April 2013
Release for consultation 25 April 2013
End of consultation (deadline for comments) 25 June 2013
Revised draft Revision 1 finalised by the Agency in collaboration with
Member States
23 October 2013
Revised draft Revision 1 agreed by ERMS FG 11 November 2013
Revised draft Revision 1 adopted by Executive Director as final 9 December 2013
Date for coming into effect of Revision 1* (for PSURs with data lock point
after 12 December 2013)
13 December 2013
*Note: Revision 1 contains the following:
- updates in VII.B and VII.C.5. following finalisation of the ICH-E2C(R2) guideline on “Periodic Benefit-
Risk Evaluation Report (PBRER)”, which reached Step 4 of the ICH process in November 2012, in order
to harmonise the principles and agreements reached by the ICH Expert Working Group;
- further guidance regarding technical aspects on the implementation of Regulation (EU) No 1235/2010
and Directive 2010/84/EU based on the experience gained since July 2012;
- practical instructions for the application, description and maintenance of the EU reference date list in
VII.C.3.2., VII.C.3.3. and VII.C.3.4. and amendments to the marketing authorisation in VII.C.3.7.;
- further instructions regarding the PSUR assessment process, product information and transitional
arrangements within the EU regulatory network in VII.C..
See websites for contact details
European Medicines Agency www.ema.europa.eu
Heads of Medicines Agencies www.hma.eu
The European Medicines Agency is
an agency of the European Union
© European Medicines Agency and Heads of Medicines Agencies, 2013.
Reproduction is authorised provided the source is acknowledged.
TABLE OF CONTENTS
VII.A. Introduction ...................................................................................... 5
VII.B. Structures and processes .................................................................. 6
VII.B.1. Objectives of the periodic update safety report (PSUR) ........................................ 6
VII.B.2. Principles for the evaluation of the risk-benefit balance within PSURs and scope of
the information to be included ...................................................................................... 7
VII.B.3. Principles for the preparation of PSURs .............................................................. 8
VII.B.4. Reference information ..................................................................................... 8
VII.B.5. Format and contents of the PSUR .................................................................... 10
VII.B.5.1. PSUR section “Introduction” ........................................................................ 13
VII.B.5.2. PSUR section “Worldwide marketing authorisation status" ............................... 13
VII.B.5.3. PSUR section “Actions taken in the reporting interval for safety reasons” .......... 13
VII.B.5.4. PSUR section “Changes to reference safety information” ................................. 15
VII.B.5.5. PSUR section “Estimated exposure and use patterns” ..................................... 15
VII.B.5.5.1. PSUR sub-section “Cumulative subject exposure in clinical trials” .................. 15
VII.B.5.5.2. PSUR sub-section “Cumulative and interval patient exposure from marketing
experience” .............................................................................................................. 16
VII.B.5.6. PSUR section “Data in summary tabulations” ................................................. 17
VII.B.5.6.1. PSUR sub-section “Reference information” .................................................. 17
VII.B.5.6.2. PSUR sub-section “Cumulative summary tabulations of serious adverse events
from clinical trials” .................................................................................................... 18
VII.B.5.6.3. PSUR sub-section “Cumulative and interval summary tabulations from post-
marketing data sources” ............................................................................................ 18
VII.B.5.7. PSUR section “Summaries of significant findings from clinical trials during the
reporting interval” ..................................................................................................... 19
VII.B.5.7.1. PSUR sub-section “Completed clinical trials” ............................................... 20
VII.B.5.7.2. PSUR sub-section “Ongoing clinical trials” ................................................... 20
VII.B.5.7.3. PSUR sub-section “Long term follow-up” .................................................... 20
VII.B.5.7.4. PSUR sub-section “Other therapeutic use of medicinal product” ..................... 20
VII.B.5.7.5. PSUR sub-section “New safety data related to fixed combination therapies” .... 20
VII.B.5.8. PSUR section “Findings from non-interventional studies” ................................. 21
VII.B.5.9. PSUR section “Information from other clinical trials and sources” ..................... 21
VII.B.5.9 1. PSUR sub-section “Other clinical trials”....................................................... 21
VII.B.5.9 2. PSUR sub-section “Medication errors” ........................................................ 21
VII.B.5.10. PSUR section “Non-clinical data” ................................................................. 21
VII.B.5.11. PSUR section “Literature” .......................................................................... 22
VII.B.5.12. PSUR section “Other periodic reports” ......................................................... 22
VII.B.5.13. PSUR section “Lack of efficacy in controlled clinical trials” .............................. 22
VII.B.5.14. PSUR section “Late-breaking information” ................................................... 23
VII.B.5.15. PSUR section “Overview of signals: new, ongoing, or closed” ......................... 23
VII.B.5.16. PSUR section “Signal and risk evaluation” .................................................... 24
VII.B.5.16.1. PSUR sub-section “Summary of safety concerns” ....................................... 25
VII.B.5.16.2. PSUR sub-section “Signal evaluation” ....................................................... 26
VII.B.5.16.3. PSUR sub-section “Evaluation of risks and new information” ....................... 27
VII.B.5.16.4. PSUR sub-section “Characterisation of risks” ............................................. 28
VII.B.5.16.5. PSUR sub-section: “Effectiveness of risk minimisation (if applicable)” ........... 29
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EMA/816292/2011 Rev 1 Page 2/68
VII.B.5.17. PSUR section “Benefit evaluation” ............................................................... 29
VII.B.5.17.1. PSUR sub-section “Important baseline efficacy and effectiveness information”
.............................................................................................................................. 29
VII.B.5.17.2. PSUR sub-section “Newly identified information on efficacy and effectiveness”
.............................................................................................................................. 29
VII.B.5.17.3. PSUR sub-section “Characterisation of benefits” ........................................ 30
VII.B.5.18. PSUR section “Integrated benefit-risk analysis for authorised indications” ........ 30
VII.B.5.18.1. PSUR sub-section “Benefit-risk context - medical need and important
alternatives”............................................................................................................. 31
VII.B.5.18.2. PSUR sub-section “Benefit-risk analysis evaluation” ................................... 31
VII.B.5.19. PSUR section “Conclusions and actions” ...................................................... 32
VII.B.5.20. Appendices to the PSUR ............................................................................ 32
VII.B.5.21. Mapping signals and risks to PSUR sections/sub-sections ............................... 33
VII.B.6. Quality systems for PSURs at the level of marketing authorisation holders ........... 34
VII.B.7. Training of staff members related to the PSUR process ...................................... 35
VII.C. Operation of the EU network ........................................................... 35
VII.C.1. PSUR process in the EU - General process ........................................................ 35
VII.C.2. Standard submission schedule of PSURs .......................................................... 37
VII.C.3. List of European Union reference dates and frequency of submission of PSURs ..... 37
VII.C.3.1. Objectives of the EU reference dates list ....................................................... 37
VII.C.3.2. Description of the EU reference dates list ...................................................... 38
VII.C.3.3. Application of the list of EU reference dates to submission of PSURs ................. 39
VII.C.3.3.1. Submission of PSURs for medicinal products: general requirement ................ 39
VII.C.3.3.2. Submission of PSURs for generic, well-established use, traditional herbal and
homeopathic medicinal products ................................................................................. 40
VII.C.3.3.3. Submission of PSURs for fixed dose combination products ............................ 42
VII.C.3.3.4. Submission of PSURs on demand of a competent authority in a Member State 42
VII.C.3.4. Criteria used for defining the frequency of submission of PSURs ....................... 42
VII.C.3.5. Maintenance of the list of EU reference dates ................................................. 43
VII.C.3.5.1. General principles .................................................................................... 43
VII.C.3.5.2. Requests from marketing authorisation holders to amend the list of EU
reference dates ........................................................................................................ 45
VII.C.3.6. Publication of the list .................................................................................. 45
VII.C.3.7. Amendment of the marketing authorisation according to the list of EU reference
dates ....................................................................................................................... 45
VII.C.4. Processes for PSUR Assessment in the EU network ............................................ 45
VII.C.4.1. PSURs for purely nationally authorised medicinal products .............................. 46
VII.C.4.2. Medicinal products authorised in more than one Member State ........................ 47
VII.C.4.2.1. Assessment of PSURs for a single centrally authorised medicinal product ....... 47
VII.C.4.2.2. Assessment of PSURs for medicinal products subject to different marketing
authorisations containing the same active substance (EU single assessment) ................... 50
VII.C.4.2.3. Single assessment including at least one centrally authorised product leading to
a CHMP opinion ........................................................................................................ 53
VII.C.4.2.4. Single assessment not including centrally authorised product leading to a CMDh
position ................................................................................................................... 55
VII.C.4.3. Relationship between PSUR and risk management plan ................................... 56
VII.C.4.3.1. PSUR and risk management plan – common modules .................................. 56
VII.C.5. EU-specific requirements for periodic safety update reports ................................ 57
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EMA/816292/2011 Rev 1 Page 3/68
VII.C.5.1. PSUR EU regional appendix, sub-section “Proposed product information” .......... 57
VII.C.5.2. PSUR EU regional appendix, sub-section “Proposed additional pharmacovigilance
and risk minimisation activities” .................................................................................. 58
VII.C.5.3. PSUR EU regional appendix, sub-section “Summary of ongoing safety concerns” 58
VII.C.5.4. PSUR EU regional appendix, sub-section “Reporting of results from post-
authorisation safety studies” ...................................................................................... 58
VII.C.5.5. PSUR EU regional appendix, sub-section “Effectiveness of risk minimisation” ..... 58
VII.C.6. Quality systems and record management systems for PSURs in the EU network ... 59
VII.C.6.1. Quality systems and record management systems at the level of the marketing
authorisation holder .................................................................................................. 59
VII.C.6.2. Quality systems and record management systems at the level of the European
Medicines Agency...................................................................................................... 60
VII.C.6.3. Quality systems and record management systems at the level of the competent
authorities in Member States ...................................................................................... 61
VII.C.7. Transparency ............................................................................................... 62
VII.C.7.1. Publication of PSUR-related documents on the European medicines and national
medicines web-portals ............................................................................................... 62
VII.C.8. Renewal of marketing authorisations ............................................................... 62
VII.C.9. Transition and interim arrangements ............................................................... 63
VII.C.9.1. Submission and availability of documents before the Agency’s repository is in
place ....................................................................................................................... 63
VII.C.9.2. Quality systems and record management systems at the level of the competent
authorities in Member States ...................................................................................... 64
VII.C.9.3. Publication of the EU list of union references dates and start of the EU- PSUR
single assessment procedure ...................................................................................... 64
VII.APPENDICES ....................................................................................... 65
VII.Appendix 1. Examples of tabulations for estimated exposure and adverse
events/reactions data ................................................................................................ 65
VII.Appendix 2. Example of tabular summary of safety signals that were ongoing or closed
during the reporting interval....................................................................................... 67
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VII.A. Introduction
Periodic safety update reports (PSURs) are pharmacovigilance documents intended to provide an
evaluation of the risk-benefit balance of a medicinal product for submission by marketing authorisation
holders at defined time points during the post-authorisation phase.
The legal requirements for submission of PSURs are established in Regulation (EC) No 726/2004,
Directive 2001/83/EC and in the Commission Implementing Regulation (EU) No 520/2012 on the
performance of pharmacovigilance activities provided for in Regulation (EC) No 726/2004 and Directive
2001/83/EC (hereinafter referred to as IR). All applicable legal requirements in this Module are
referenced in the way explained in the GVP Introductory Cover Note and are usually identifiable by the
modal verb “shall”. Guidance for the implementation of legal requirements is provided using the modal
verb “should”.
The format of PSURs shall follow the structure described in the IR Article 35. This Module provides
guidance on the preparation, submission and assessment of PSURs.
The scope, objectives, format and content of the PSUR are described in VII.B.. The required format
and content of PSURs in the EU are based on those for the Periodic Benefit Risk Evaluation Report
(PBRER) described in the ICH-E2C(R2) guideline (see Annex IV ICH-E2C(R2)). The PBRER format
replaces the PSUR format previously described in the ICH-E2C(R1). In line with the EU legislation, the
report is described as PSUR in the GVP Modules.
Further details and guidance for the submission of PSURs in the EU, including the list of Union
references dates and frequency of submission are provided in VII.C., which also covers the single EU
assessment of PSURs in VII.C.4.. Details related to the quality system are provided in VII.C.6. and the
publication of PSUR-related documents in VII.C.7. as transparency provisions.
Each marketing authorisation holder shall be responsible for submitting PSURs for its own products
[DIR Art 107b] [REG Art 28 (2)] and should submit PSURs to the Agency (see VII.C.9. for transitional
arrangements) according to the following timelines:
• within 70 calendar days of the data lock point (day 0) for PSURs covering intervals up to 12
months (including intervals of exactly 12 months); and
• within 90 calendar days of the data lock point (day 0) for PSURs covering intervals in excess of 12
months;
• the timeline for the submission of ad hoc PSURs requested by competent authorities will normally
be specified in the request, otherwise the ad hoc PSURs should be submitted within 90 calendar
days of the data lock point.
It should be noted that detailed listings of individual cases shall not be included systematically [IR Art
34(4)]. The PSUR should focus on summary information, scientific safety assessment and integrated
benefit-risk evaluation.
Recital 23 of Directive 2010/84/EU states that the obligations imposed in respect of PSURs should be
proportionate to the risks posed by medicinal products. PSUR reporting should therefore be linked to
the risk management systems of a medicinal product (see Module V). The “modular approach” of the
PSUR described in VII.B.5. aims to minimise duplication and improve efficiency during the preparation
and review of PSURs along with other regulatory documents such as the development safety update
report (DSUR)1 or the safety specification in the Risk Management Plan (RMP), by enabling the
1 See Detailed Guidance on the Collection, Verification and Presentation of Adverse Event/Reaction Reports Arising from
Clinical Trials on Medicinal Products for Human Use; available on http://ec.europa.eu/health/documents/eudralex/vol-10/
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1)
EMA/816292/2011 Rev 1 Page 5/68
http://ec.europa.eu/health/documents/eudralex/vol-10/
common content of particular sections where appropriate to be utilised interchangeably across different
PSURs, DSURs and RMPs.
The amended Directive 2001/83/EC also waives the obligation to submit PSURs routinely for generic
medicinal products (authorised under DIR Art 10(1)), well-established use medicinal products
(authorised under DIR Art 10a), homeopathic medicinal products (authorised under DIR Art 14) and
traditional herbal medicinal products (authorised under DIR Art 16a), [DIR Art 107b(3)]. For such
products, PSURs shall be submitted where there is a condition in the marketing authorisation or when
requested by a competent authority in a Member State on the basis of concerns relating to
pharmacovigilance data or due to the lack of PSURs for an active substance after its authorisation [DIR
Art 107b(3)(a) and (3)(b)].
Competent authorities in the Member States shall assess PSURs to determine whether there are new
risks or whether risks have changed or whether there are changes to the risk-benefit balance of
medicinal products [DIR Art 107d].
In order to increase the shared use of resources between competent authorities in Member States, a
single assessment of PSURs should be performed in the EU for different medicinal products containing
the same active substance or the same combination of active substances authorised in more than one
Member State for which a Union reference date and frequency of submission of PSURs has been
established. The EU single assessment can include joint assessment for medicinal products authorised
through either national or centralised procedures for marketing authorisation. The Agency shall make
available a list of Union reference dates and frequency of submission [REG Art 26(g)] which will be
legally binding.
As part of the assessment, it should be considered whether further investigations need to be carried
out and whether any action concerning the marketing authorisations of products containing the same
active substance or the same combination of active substances, and their product information is
necessary.
The Agency shall make the PSURs available to the competent authorities in Member States, members
of the Pharmacovigilance Risk Assessment Committee (PRAC), of the Committee for Medicinal Products
for Human use (CHMP) and of the Coordination Group for Mutual Recognition and Decentralised
Procedures - Human (CMDh) and the European Commission by means of a PSUR repository [DIR Art
107b(2)].
VII.B. Structures and processes
VII.B.1. Objectives of the periodic update safety report (PSUR)
The main objective of a PSUR is to present a comprehensive, concise and critical analysis of the risk-
benefit balance of the medicinal product taking into account new or emerging information in the
context of cumulative information on risks and benefits. The PSUR is therefore a tool for post-
authorisation evaluation at defined time points in the lifecycle of a product.
For the purposes of lifecycle benefit-risk management, it is necessary to continue evaluating the risks
and benefits of a medicine in everyday medical practice and long term use in the post-authorisation
phase. This may extend to evaluation of populations and endpoints that could not be investigated in
the pre-authorisation clinical trials. A different risk-benefit balance may emerge as pharmacovigilance
reveals further information about safety. The marketing authorisation holder should therefore re-
evaluate the risk-benefit balance of its own medicinal products in populations exposed. This structured
evaluation should be undertaken in the context of ongoing pharmacovigilance (see Module XII) and
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1)
EMA/816292/2011 Rev 1 Page 6/68
risk management (see Module V) to facilitate optimisation of the risk-benefit balance through effective
risk minimisation.
Urgent safety information should be reported through the appropriate mechanism. A PSUR is not
intended, in the first instance, for notification of significant new safety or efficacy information or to
provide the means by which new safety issues are detected, (see Module IX and XII). It is
acknowledged that the review of the data in the PSUR may lead to new safety issues being identified.
VII.B.2. Principles for the evaluation of the risk-benefit balance within
PSURs and scope of the information to be included
Benefit-risk evaluation should be carried out throughout the lifecycle of the medicinal product to
promote and protect public health and to enhance patient safety through effective risk minimisation.
After a marketing authorisation is granted, it is necessary to continue evaluating the benefits and risks
of medicinal products in actual use and/or long term use, to confirm that the risk-benefit balance
remains favourable.
The analysis of the risk-benefit balance should incorporate an evaluation of the safety, efficacy and
effectiveness information that becomes available2, with reasonable and appropriate effort, during the
reporting interval for the medicinal product in the context of what was known previously.
The risk evaluation should be based on all uses of the medicinal product. The scope includes evaluation
of safety in real medical practice including use in unauthorised indications and use which is not in line
with the product information. If use of the medicinal product is identified where there are critical gaps
in knowledge for specific safety issues or populations, such use should be reported in the PSUR (e.g.
use in paediatric population or in pregnant women). Sources of information on use outside
authorisation may include drug utilisation data, information from spontaneous reports and publications
in the literature.
The scope of the benefit information should include both clinical trial and real world data in authorised
indications.
The integrated benefit-risk evaluation should be performed for all authorised indications and should
incorporate the evaluation of risks in all use of the medicinal product (including use in unauthorised
indications).
The evaluation should involve:
1. Critically examining the information which has emerged during the reporting interval to determine
whether it has generated new signals, led to the identification of new potential or identified risks or
contributed to knowledge of previously identified risks.
2. Critically summarising relevant new safety, efficacy and effectiveness information that could have
an impact on the risk-benefit balance of the medicinal product.
3. Conducting an integrated benefit-risk analysis for all authorised indications based on the
cumulative information available since the development international birth date (DIBD), the date of
first authorisation for the conduct of an interventional clinical trial in any country. For the cases
where the DIBD is unknown or the marketing authorisation holder does not have access to data
from the clinical development period, the earliest possible applicable date should be used as
starting point for the inclusion and evaluation of the cumulative information.
2 The ICH-E2C(R2) guideline should not serve to limit the scope of the information to be provided in the benefit-risk
evaluation of a medicinal product. Please refer to the applicable laws and regulations in the countries and regions.
For EU specific requirements, see VII.C.5..
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4. Summarising any risk minimisation actions that may have been taken or implemented during the
reporting interval, as well as risk minimisation actions that are planned to be implemented.
5. Outlining plans for signal or risk evaluations including timelines and/or proposals for additional
pharmacovigilance activities.
VII.B.3. Principles for the preparation of PSURs
Unless otherwise specified by competent authorities, the marketing authorisation holder shall prepare
a single PSUR for all its medicinal products containing the same active substance with information
covering all the authorised indications, route of administration, dosage forms and dosing regiments,
irrespective of whether authorised under different names and through separate procedures. Where
relevant, data relating to a particular indication, dosage form, route of administration or dosing
regimen, shall be presented in a separate section of the PSUR and any safety concerns shall be
addressed accordingly [IR Art 34(6)]. There might be exceptional scenarios where the preparation of
separate PSURs might be appropriate, for instance, in the event of different formulations for entirely
different indications. In this case, agreement should be obtained from the relevant competent
authorities preferably at the time of authorisation.
Case narratives shall be provided in the relevant risk evaluation section of the PSUR where integral to
the scientific analysis of a signal or safety concern [IR Art 34(4)]. In this context, the term “case
narratives” refers to clinical evaluations of individual cases rather than the CIOMS narratives. It should
not be necessary to provide the actual CIOMS narrative text included in the individual case safety
report (ICSR) but rather a clinical evaluation of important or illustrative cases in the context of the
evaluation of the safety concern/signal.
When data received at the marketing authorisation holder from a partner might contribute
meaningfully to the safety, benefit and/or benefit-risk analyses and influence the reporting marketing
authorisation holder’s product information, these data should be included and discussed in the PSUR.
The format and table of contents of all PSURs shall be as described in the IR Art 35 and each report
should include interval as well as cumulative data. As the PSUR should be a single stand–alone
document for the reporting interval, based on cumulative data, summary bridging reports and
addendum reports, introduced in ICH-E2C(R1) guideline, will not be accepted.
The GVP Modules on Product- or Population-Specific Considerations3 should be consulted as applicable
when preparing a PSUR.
VII.B.4. Reference information
Risk minimisation activities evaluated in the PSUR include updates to the product information.
The reference product information for the PSUR should include “core safety” and “authorised
indications” components. In order to facilitate the assessment of benefit and risk-benefit balance by
indication in the evaluation sections of the PSUR, the reference product information document should
list all authorised indications in ICH countries4 or regions. When the PSUR is also submitted to other
countries in which there are additional locally authorised indications, these indications may be either
added to the reference product information or handled as a regional appendix as considered most
appropriate by the marketing authorization holder. The basis for the benefit evaluation should be the
baseline important efficacy and effectiveness information summarised in the PSUR section 17.1
(“Important baseline efficacy and effectiveness information”).
3 http://www.ema.europa.eu
4 http://www.ich.org/
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Information related to a specific indication, formulation or route of administration should be clearly
identified in the reference product information.
The following possible options can be considered by the marketing authorisation holders when
selecting the most appropriate reference product information for a PSUR:
• Company core data sheet (CCDS)
− It is common practice for marketing authorisation holders to prepare their own company core
data sheet which covers data relating to safety, indications, dosing, pharmacology, and other
information concerning the product. The core safety information contained within the CCDS is
referred to as the company core safety information (CCSI). A practical option for the purpose
of the PSUR is for each marketing authorisation holder to use the CCDS in effect at the end of
the reporting interval, as reference product information for both the risk sections of the PSUR
as well as the main authorised indications for which benefit is evaluated.
− When the CCDS does not contain information on authorised indications, the marketing
authorisation holder should clearly specify which document is used as reference information for
the authorised indications in the PSUR.
• Other options for the reference product information
− When no CCDS or CCSI exist for a product (e.g. where the product is authorised in only one
country or region, or for established/generics products on the market for many years), the
marketing authorisation holder should clearly specify the reference information being used.
This may comprise national or regional product information such as the EU summary of product
characteristics (SmPC).
− Where the reference information for the authorised indications is a separate document to the
reference safety information (the core safety information contained within the reference
product information), the version in effect at the end of the reporting interval should be
included as an appendix to the PSUR (see VII.B.5.20.).
The marketing authorisation holder should continuously evaluate whether any revision of the reference
product information/reference safety information is needed whenever new safety information is
obtained during the reporting interval and ensure that significant changes made over the interval are
described in PSUR section 4 (“Changes to the reference safety information”) and where relevant,
discussed in PSUR section 16 (“Signal and risk evaluation”). These changes may include:
• changes to contraindications, warnings/precautions sections;
• addition to adverse reactions and interactions;
• addition of important new information on use in overdose; and
• removal of an indication or other restrictions for safety or lack of efficacy reasons.
The marketing authorisation holder should provide a clean copy of all versions of the reference product
information in effect at the end of the reporting interval (e.g. different formulations included in the
same PSUR) as an appendix to the PSUR (see VII.B.5.20.). The reference product information should
be dated and version controlled.
Where new information on safety that could warrant changes to the authorised product information
(e.g. new adverse drug reaction, warning or contraindication) has been added to the reference safety
information during the period from the data lock point to the submission of the PSUR, this information
should be included in the PSUR section 14 (“Late-breaking information”), if feasible.
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If stipulated by applicable regional requirements, the marketing authorisation holder should provide, in
the regional appendix, information on any final, ongoing and proposed changes to the national or local
authorised product information (see VII.C.5.)
VII.B.5. Format and contents of the PSUR
The PSUR shall be based on all available data and shall focus on new information which has emerged
since the data lock point of the last PSUR [IR Art 34(1)]. Cumulative information should be taken into
account when performing the overall safety evaluation and integrated benefit-risk assessment.
Because clinical development of a medicinal product frequently continues following marketing
authorisation, relevant information from post-authorisation studies or clinical trials in unauthorised
indications or populations should also be included in the PSUR. Similarly, as knowledge of the safety of
a medicinal product may be derived from evaluation of other data associated with off-label use, such
knowledge should be reflected in the risk evaluation where relevant and appropriate.
The PSUR shall provide summaries of data relevant to the benefits and risks of the medicinal product,
including results of all studies with a consideration of their potential impact on the marketing
authorisation [DIR Art 107b(1)(a)].
Examples of sources of efficacy, effectiveness and safety information that may be used in the
preparation of PSURs include the following:
• non-clinical studies;
• spontaneous reports (e.g. on the marketing authorisation holder’s safety database);
• active surveillance systems (e.g. sentinel sites);
• investigations of product quality;
• product usage data and drug utilisation information;
• clinical trials, including research in unauthorised indications or populations;
• observational studies, including registries;
• patient support programs;
• systematic reviews and meta-analysis;
• marketing authorisation holders sponsored websites5;
• published scientific literature or reports from abstracts, including information presented at scientific
meetings;
• unpublished manuscripts;
• licensing partners, other sponsors or academic institutions and research networks;
• competent authorities (worldwide).
The above list is not intended to be all inclusive, and additional data sources may be used by the
marketing authorisation holder to present safety, efficacy and effectiveness information in the PSUR
and to evaluate the risk-benefit balance, as appropriate to the product and its known and emerging
important benefits and risks. When desired by the marketing authorisation holder, a list of the sources
of information used to prepare the PSUR can be provided as an appendix to the PSUR.
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A PSUR shall be prepared following the full modular structure set out in Annex II of the IR [IR Art 35].
For the purposes of this Module, sources of information include data regarding the active substance(s)
included in the medicinal product, or the medicinal product that the marketing authorisation holder
may reasonably be expected to have access to and that are relevant to the evaluation of the safety,
and/or risk-benefit balance. It is therefore recognised that while the same format (as defined in the IR)
shall be followed for all products, the extent of the information provided may vary where justified
according to what is accessible to the marketing authorisation holder. For example, for a marketing
authorisation holder sponsored clinical trial, there should be access to patient level data while for a
clinical trial not sponsored by the marketing authorisation holder, only the published report may be
accessible.
The level of detail provided in certain sections of the PSUR should depend on known or emerging
important information on the medicinal product’s benefits and risks. This approach is applicable to
those sections of the PSUR in which there is evaluation of information about safety, efficacy,
effectiveness, safety signals and risk-benefit balance.
When preparing the PSUR, the ICH-E2C(R2) guideline (see Annex IV ICH-E2C(R2)) on PBRER should
also be applied. Guidance on the titles, order and content of the PSUR sections is provided in VII.B.5.1.
to VII.B.5.21.. When no relevant information is available for any of the sections, this should be stated.
• Part I: Title page including signature6
• Part II: Executive Summary
• Part III: Table of Contents
1. Introduction
2. Worldwide marketing authorisation status
3. Actions taken in the reporting interval for safety reasons
4. Changes to reference safety information
5. Estimated exposure and use patterns
5.1. Cumulative subject exposure in clinical trials
5.2. Cumulative and interval patient exposure from marketing experience
6. Data in summary tabulations
6.1. Reference information
6.2. Cumulative summary tabulations of serious adverse events from clinical trials
6.3. Cumulative and interval summary tabulations from post-marketing data sources
7. Summaries of significant findings from clinical trials during the reporting interval
7.1. Completed clinical trials
7.2. Ongoing clinical trials
7.3. Long-term follow-up
7.4. Other therapeutic use of medicinal product
6 For PSURs submission in the EU, it is at the discretion of the QPPV to determine the most appropriate person to sign the
document according to the marketing authorisation holder structure and responsibilities. A statement confirming the
designation by the QPPV should be included. No delegation letters should be submitted.
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7.5. New safety data related to fixed combination therapies
8. Findings from non-interventional studies
9. Information from other clinical trials and sources
9.1. Other clinical trials
9.2. Medication errors
10. Non-clinical Data
11. Literature
12. Other periodic reports
13. Lack of efficacy in controlled clinical trials
14. Late-breaking information
15. Overview of signals: new, ongoing or closed
16. Signal and risk evaluation
16.1. Summaries of safety concerns
16.2. Signal evaluation
16.3. Evaluation of risks and new information
16.4. Characterisation of risks
16.5. Effectiveness of risk minimisation (if applicable)
17. Benefit evaluation
17.1. Important baseline efficacy and effectiveness information
17.2. Newly identified information on efficacy and effectiveness
17.3. Characterisation of benefits
18. Integrated benefit-risk analysis for authorised indications
18.1. Benefit-risk context – Medical need and important alternatives
18.2. Benefit-risk analysis evaluation
19. Conclusions and actions
20. Appendices to the PSUR
PSUR title page
The title page should include the name of the medicinal product(s)7 and substance, international birth
date (IBD) (the date of the first marketing authorisation for any product containing the active
substance granted to any company in any country in the world), reporting interval, date of the report,
marketing authorisation holder details and statement of confidentiality of the information included in
the PSUR.
The title page shall also contain the signature.
7 For PSURs covering multiple products, for practical reasons, this information may be provided in the PSUR Cover Page
(See Annex II)
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PSUR executive summary
An executive summary should be placed immediately after the title page and before the table of
contents. The purpose of the executive summary is to provide a concise summary of the content and
the most important information in the PSUR and should contain the following information:
• introduction and reporting interval;
• medicinal product(s), therapeutic class(es), mechanism(s) of action, indication(s), pharmaceutical
formulation(s), dose(s) and route(s) of administration;
• estimated cumulative clinical trials exposure;
• estimated interval and cumulative exposure from marketing experience;
• number of countries in which the medicinal product is authorised;
• summary of the overall benefit-risk analysis evaluation (based on sub-section 18.2 “benefit-risk
analysis evaluation” of the PSUR);
• actions taken and proposed for safety reasons, (e.g. significant changes to the reference product
information, or other risk minimisation activities);
• conclusions.
PSUR table of contents
The executive summary should be followed by the table of contents.
VII.B.5.1. PSUR section “Introduction”
The marketing authorisation holder should briefly introduce the product(s) so that the PSUR “stands
alone” but it is also placed in perspective relative to previous PSURs and circumstances. The
introduction should contain the following information:
• IBD, and reporting interval;
• medicinal product(s), therapeutic class(es), mechanism(s) of action, authorised indication(s),
pharmaceutical form(s), dose(s) and route(s) of administration;
• a brief description of the population(s) being treated and studied;
VII.B.5.2. PSUR section “Worldwide marketing authorisation status"
This section of the PSUR should contain a brief narrative overview including: date of the first
authorisation worldwide, indications(s), authorised dose(s), and where authorised.
VII.B.5.3. PSUR section “Actions taken in the reporting interval for safety
reasons”
This section of the PSUR should include a description of significant actions related to safety that have
been taken worldwide during the reporting interval, related to either investigational uses or marketing
experience by the marketing authorisation holder, sponsors of clinical trial(s), data monitoring
committees, ethics committees or competent authorities that had either:
• a significant influence on the risk-benefit balance of the authorised medicinal product; and/or
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• an impact on the conduct of a specific clinical trial(s) or on the overall clinical development
programme.
If known, the reason for each action should be provided and any additional relevant information should
be included as appropriate. Relevant updates to previous actions should also be summarised in this
section.
Examples of significant actions taken for safety reasons include:
Actions related to investigational uses:
• refusal to authorise a clinical trial for ethical or safety reasons;
• partial8 or complete clinical trial suspension or early termination of an ongoing clinical trial because
of safety findings or lack of efficacy;
• recall of investigational drug or comparator;
• failure to obtain marketing authorisation for a tested indication including voluntary withdrawal of a
marketing authorisation application;
• risk management activities, including:
− protocol modifications due to safety or efficacy concerns (e.g. dosage changes, changes in
study inclusion/exclusion criteria, intensification of subject monitoring, limitation in trial
duration);
− restrictions in study population or indications;
− changes to the informed consent document relating to safety concerns;
− formulation changes;
− addition by regulators of a special safety-related reporting requirement;
− issuance of a communication to investigators or healthcare professionals; and
− plans for new studies to address safety concerns.
Actions related to marketing experience:
• failure to obtain or apply for a marketing authorisation renewal;
• withdrawal or suspension of a marketing authorisation;
• actions taken due to product defects and quality issues;
• suspension of supply by the marketing authorisation holder;
• risk management activities including:
− significant restrictions on distribution or introduction of other risk minimisation measures;
− significant safety-related changes in labelling documents including restrictions on use or
population treated;
− communications to health care professionals; and
− new post-marketing study requirement(s) imposed by competent authorities.
8“Partial suspension” might include several actions (e.g. suspension of repeat dose studies, but continuation of single dose
studies; suspension of trials in one indication, but continuation in another, and/or suspension of a particular dosing regimen
in a trial but continuation of other doses). ICH-E2C(R2) guideline (see Annex IV).
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VII.B.5.4. PSUR section “Changes to reference safety information”
This PSUR section should list any significant changes made to the reference safety information within
the reporting interval. Such changes might include information relating to contraindications, warnings,
precautions, serious adverse drug reactions, interactions, important findings from ongoing or
completed clinical trials and significant non-clinical findings (e.g. carcinogenicity studies). Specific
information relevant to these changes should be provided in the appropriate sections of the PSUR.
VII.B.5.5. PSUR section “Estimated exposure and use patterns”
PSURs shall provide an accurate estimate of the population exposed to the medicinal product, including
all data relating to the volume of sales and volume of prescriptions. This estimate of exposure shall be
accompanied by a qualitative and quantitative analysis of actual use, which shall indicate, where
appropriate, how actual use differs from the indicated use based on all data available to the marketing
authorisation holder, including the results of observational or drug utilisation studies [IR Art 34 (2)].
This PSUR section should provide estimates of the size and nature of the population exposed to the
medicinal product including a brief description of the method(s) used to estimate the subject/patient
exposure and the limitations of that method.
Consistent methods for calculating subject/patient exposure should be used across PSURs for the same
medicinal product. If a change in the method is appropriate, both methods and calculations should be
provided in the PSUR introducing the change and any important difference between the results using
the two methods should be highlighted.
VII.B.5.5.1. PSUR sub-section “Cumulative subject exposure in clinical trials”
This section of the PSUR should contain the following information on the patients studied in clinical
trials sponsored by the marketing authorisation holder, if applicable presented in tabular formats:
• cumulative numbers of subjects from ongoing and completed clinical trials exposed to the
investigational medicinal product, placebo, and/or active comparator(s) since the DIBD. It is
recognised that for “old products”, detailed data might not be available;
• more detailed cumulative subject exposure in clinical trials should be presented if available (e.g.
sub-grouped by age, sex, and racial/ethnic group for the entire development programme);
• important differences among trials in dose, routes of administration, or patient populations can be
noted in the tables, if applicable, or separate tables can be considered;
• if clinical trials have been or are being performed in special populations (e.g. pregnant women;
patients with renal, hepatic, or cardiac impairment; or patients with relevant genetic
polymorphisms), exposure data should be provided as appropriate;
• when there are substantial differences in time of exposure between subjects randomised to the
investigational medicinal product or comparator(s), or disparities in length of exposure between
clinical trials, it can be useful to express exposure in subject-time (subject-days, -months, or -
years);
• investigational drug exposure in healthy volunteers might be less relevant to the overall safety
profile, depending on the type of adverse reaction, particularly when subjects are exposed to a
single dose. Such data can be presented separately with an explanation as appropriate;
• if the serious adverse events from clinical trials are presented by indication in the summary
tabulations, the patient exposure should also be presented by indication, where available;
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• for individual trials of particular importance, demographic characteristics should be provided
separately.
Examples of tabular format for the estimated exposure in clinical trials are presented in VII. Appendix
1, Tables VII.2, VII.3 and VII.4.
VII.B.5.5.2. PSUR sub-section “Cumulative and interval patient exposure from marketing
experience”
Separate estimates should be provided for cumulative exposure (since the IBD), when possible, and
interval exposure (since the data lock point of the previous PSUR). Although it is recognised that it is
often difficult to obtain and validate exposure data, the number of patients exposed should be provided
whenever possible, along with the method(s) used to determine the estimate. Justification should be
provided if it is not possible to estimate the number of patients exposed. In this case, alternative
estimates of exposure, if available, should be presented along with the method(s) used to derive them.
Examples of alternative measures of exposure include patient-days of exposure and number of
prescriptions. Only if such measures are not available, measures of drug sales, such as tonnage or
dosage units, may be used. The concept of a defined daily dose may also be used to arrive at patient
exposure estimates.
The data should be presented according to the following categories:
1. Post-authorisation (non-clinical trial) exposure:
An overall estimation of patient exposure should be provided. In addition, the data should be
routinely presented by sex, age, indication, dose, formulation and region, where applicable.
Depending upon the product, other variables may be relevant, such as number of vaccination
courses, route(s) of administration, and duration of treatment.
When there are patterns of reports indicating a safety signal, exposure data within relevant
subgroups should be presented, if possible.
2. Post-authorisation use in special populations:
Where post-authorisation use has occurred in special populations, available information regarding
cumulative patient numbers exposed and the method of calculation should be provided. Sources of
such data may include for instance non-interventional studies designed to obtain this information,
including registries. Other sources of information may include data collection outside a study
environment including information collected through spontaneous reporting systems (e.g.
information on reports of pregnancy exposure without an associated adverse event may be
summarised in this section). Populations to be considered for discussion include, but might not be
limited to:
• paediatric population;
• elderly population;
• pregnant or lactating women;
• patients with hepatic and/or renal impairment;
• patients with other relevant co-morbidity;
• patients with disease severity different from that studied in clinical trials;
• sub-populations carrying relevant genetic polymorphism(s);
• populations with specific racial and/or ethnic origins.
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3. Other post-authorisation use:
If the marketing authorisation holder becomes aware of a pattern of use of the medicinal product,
which may be regional, considered relevant for the interpretation of safety data, provide a brief
description thereof. Examples of such patterns of use may include evidence of overdose, abuse,
misuse and use beyond the recommendation(s) in the reference product information (e.g. an anti-
epileptic drug used for neuropathic pain and/or prophylaxis of migraine headaches). Where
relevant to the evaluation of safety and/or benefit-risk, information reported on patterns of use
without reference to adverse reactions should be summarised in this section as applicable. Such
information may be received via spontaneous reporting systems, medical information queries,
customer’s complaints, screening of digital media or via other information sources available to the
marketing authorisation holder. If quantitative information on use is available, it should be
provided.
If known, the marketing authorisation holder may briefly comment on whether other use beyond
the recommendation(s) in the reference product information may be linked to clinical guidelines,
clinical trial evidence, or an absence of authorised alternative treatments. For purposes of
identifying patterns of use outside the terms of the reference product information, the marketing
authorisation holder should use the appropriate sections of the reference product information that
was in effect at the end of the reporting interval of the PSUR (e.g. authorised indication, route of
administration, contraindications).
Signals or risks identified from any data or information source should be presented and evaluated
in the relevant sections of the PSUR.
Examples of tabular format for the estimated exposure from marketing experience are presented in
VII. Appendix 1, Tables VII.5 and VII.6.
VII.B.5.6. PSUR section “Data in summary tabulations”
The objective of this PSUR section is to present safety data through summary tabulations of serious
adverse events from clinical trials, spontaneous serious and non-serious reactions from marketing
experience (including reports from healthcare professionals, consumers, scientific literature, competent
authorities (worldwide)) and serious reactions from non-interventional studies and other non-
interventional solicited source. At the discretion of the marketing authorisation holder graphical
displays can be used to illustrate specific aspects of the data when useful to enhance understanding.
When the Medical Dictionary for Regulatory Activities (MedDRA) terminology is used for coding the
adverse event/reaction terms, the preferred term (PT) level and system organ class (SOC) should be
presented in the summary tabulations.
The seriousness of the adverse events/reactions in the summary tabulations should correspond to the
seriousness assigned to events/reactions included in the ICSRs using the criteria established in ICH-
E2A9 (see Annex IV). When serious and non-serious events/reactions are included in the same ICSR,
the individual seriousness per reaction should be reflected in the summary tabulations. Seriousness
should not be changed specifically for the preparation of the PSURs.
VII.B.5.6.1. PSUR sub-section “Reference information”
This sub-section of the PSUR should specify the version(s) of the coding dictionary used for
presentation of adverse events/reactions.
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VII.B.5.6.2. PSUR sub-section “Cumulative summary tabulations of serious adverse events
from clinical trials”
This PSUR sub-section should provide background for the appendix that provides a cumulative
summary tabulation of serious adverse events reported in the marketing authorisation holder’s clinical
trials, from the DIBD to the data lock point of the current PSUR. The marketing authorisation holder
should explain any omission of data (e.g. clinical trial data might not be available for products
marketed for many years). The tabulation(s) should be organised by MedDRA SOC (listed in the
internationally agreed order), for the investigational drug, as well as for the comparator arm(s) (active
comparators, placebo) used in the clinical development programme. Data can be integrated across the
programme. Alternatively, when useful and feasible, data can be presented by trial, indication, route of
administration or other variables.
This sub-section should not serve to provide analyses or conclusions based on the serious adverse
events.
The following points should be considered:
• Causality assessment is generally useful for the evaluation of individual rare adverse drug
reactions. Individual case causality assessment has less value in the analysis of aggregate data,
where group comparisons of rates are possible. Therefore, the summary tabulations should include
all serious adverse events and not just serious adverse reactions for the investigational drug,
comparators and placebo. It may be useful to give rates by dose.
• In general, the tabulation(s) of serious adverse events from clinical trials should include only those
terms that were used in defining the case as serious and non-serious events should be included in
the study reports.
• The tabulations should include blinded and unblinded clinical trial data. Unblinded serious adverse
events might originate from completed trials and individual cases that have been unblinded for
safety-related reasons (e.g. expedited reporting), if applicable. Sponsors of clinical trials and
marketing authorisation holders should not unblind data for the specific purpose of preparing the
PSUR.
• Certain adverse events can be excluded from the clinical trials summary tabulations, but such
exclusions should be explained in the report. For example, adverse events that have been defined
in the protocol as “exempt” from special collection and entry into the safety database because they
are anticipated in the patient population, and those that represent study endpoints, can be
excluded (e.g. deaths reported in a trial of a drug for congestive heart failure where all-cause
mortality is the primary efficacy endpoint, disease progression in cancer trials).
An example of summary tabulation of serious adverse events from clinical trials can be found in VII.
Appendix 1 Table VII.7.
VII.B.5.6.3. PSUR sub-section “Cumulative and interval summary tabulations from post-
marketing data sources”
This sub-section of the PSUR should provide background for the appendix that provides cumulative and
interval summary tabulations of adverse reactions, from the IBD to the data lock point of the current
PSUR. These adverse reactions are derived from spontaneous ICSRs including reports from healthcare
professionals, consumers, scientific literature, competent authorities (worldwide) and from solicited
non-interventional ICSRs including those from non-interventional studies10. Serious and non-serious
reactions from spontaneous sources, as well as serious adverse reactions from non-interventional
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studies and other non-interventional solicited sources should be presented in a single table, with
interval and cumulative data presented side-by-side. The table should be organised by MedDRA SOC
(listed in the internationally agreed order). For special issues or concerns, additional tabulations of
adverse reactions can be presented by indication, route of administration, or other variables.
As described in ICH-E2D11 (see Annex IV) guideline, for marketed medicinal products, spontaneously
reported adverse events usually imply at least a suspicion of causality by the reporter and should be
considered to be suspected adverse reactions for regulatory reporting purposes.
Analysis or conclusions based on the summary tabulations should not be provided in this PSUR sub-
section.
An example of summary tabulations of adverse drug reactions from post-marketing data sources can
be found in VII. Appendix 1 Table VII.8.
VII.B.5.7. PSUR section “Summaries of significant findings from clinical
trials during the reporting interval”
This PSUR section should provide a summary of the clinically important emerging efficacy and safety
findings obtained from the marketing authorisation holder’s sponsored clinical trials during the
reporting interval, from the sources specified in the sub-sections listed below. When possible and
relevant, data categorised by sex and age (particularly paediatrics versus adults), indication, dose, and
region should be presented.
Signals arising from clinical trial sources should be tabulated in PSUR section 15 (“Overview on signals:
new, ongoing or closed”). Evaluation of the signals, whether or not categorised as refuted signals or
either potential or identified risk, that were closed during the reporting interval should be presented in
PSUR section 16.2 (“Signal evaluation”). New information in relation to any previously known potential
or identified risks and not considered to constitute a newly identified signal should be evaluated and
characterised in PSUR sections 16.3 (“Evaluation of risks and new information”) and 16.4
(“Characterisation of risks”) respectively.
Findings from clinical trials not sponsored by the marketing authorisation holder should be described in
the relevant sections of the PSUR.
When relevant to the benefit-risk evaluation, information on lack of efficacy from clinical trials for
treatments of non-life-threatening diseases in authorised indications should also be summarised in this
section. Information on lack of efficacy from clinical trials with products intended to treat or prevent
serious or life-threatening illness should be summarised in section 13 (“Lack of efficacy in controlled
clinical trials”) (VII.B.5.13).
Information from other clinical trials/study sources should be included in the PSUR sub-section 9.1
(“other clinical trials”) (VII.B.5.9.1).
In addition, the marketing authorisation holder should include an appendix listing the sponsored post-
authorisation interventional trials with the primary aim of identifying, characterising, or quantifying a
safety hazard or confirming the safety profile of the medicinal product that were completed or ongoing
during the reporting interval. The listing should include the following information for each trial:
• study ID (e.g. protocol number or other identifier);
• study title (abbreviated study title, if applicable);
• study type (e.g. randomised clinical trial, cohort study, case-control study);
11 ICH-E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting .
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• population studied, including country and other relevant population descriptors (e.g. paediatric
population or trial subjects with impaired renal function);
• study start (as defined by the marketing authorisation holder) and projected completion dates;
• status: ongoing (clinical trial has begun) or completed (clinical study report is finalised).
VII.B.5.7.1. PSUR sub-section “Completed clinical trials”
This sub-section of the PSUR should provide a brief summary of clinically important emerging efficacy
and safety findings obtained from clinical trials completed during the reporting interval. This
information can be presented in narrative format or as a synopsis12. It could include information that
supports or refutes previously identified safety concerns as well as evidence of new safety signals.
VII.B.5.7.2. PSUR sub-section “Ongoing clinical trials”
If the marketing authorisation holder is aware of clinically important information that has arisen from
ongoing clinical trials (e.g. learned through interim safety analyses or as a result of unblinding of
subjects with adverse events), this sub-section should briefly summarise the concern(s). It could
include information that supports or refutes previously identified safety concerns, as well as evidence
of new safety signals.
VII.B.5.7.3. PSUR sub-section “Long term follow-up”
Where applicable, this sub-section should provide information from long-term follow-up of subjects
from clinical trials of investigational drugs, particularly advanced therapy products (e.g. gene therapy,
cell therapy products and tissue engineered products).
VII.B.5.7.4. PSUR sub-section “Other therapeutic use of medicinal product”
This sub-section of the PSUR should include clinically important safety information from other
programmes conducted by the marketing authorisation holder that follow a specific protocol, with
solicited reporting as per ICH-E2D13 (e.g. expanded access programmes, compassionate use
programmes, particular patient use, and other organised data collection).
VII.B.5.7.5. PSUR sub-section “New safety data related to fixed combination therapies”
Unless otherwise specified by national or regional regulatory requirements, the following options can
be used to present data from combination therapies:
• If the active substance that is the subject of the PSURs is also authorised or under development as
a component of a fixed combination product or a multi-drug regimen, this sub-section should
summarise important safety findings from use of the combination therapy.
• If the product itself is a fixed combination product, this PSUR sub-section should summarise
important safety information arising from the individual components whether authorised or under
development.
12 Examples of synopses can be found in ICH-E3: Structure and Content of Clinical Study Reports and CIOMS VII (Council
for International Organizations of Medical Sciences (CIOMS). Development Safety Update Report (DSUR): Harmonizing the
Format and Content for Periodic Safety Reporting During Clinical Trials - Report of CIOMS Working Group VII). Geneva:
CIOMS; 2006. http://www.cioms.ch/.
13 ICH-E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting.
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The information specific to the combination can be incorporated into a separate section(s) of the PSUR
for one or all of the individual components of the combination.
VII.B.5.8. PSUR section “Findings from non-interventional studies”
This section should also summarise relevant safety information or information with potential impact in
the benefit-risk assessment from marketing authorisation holder-sponsored non-interventional studies
that became available during the reporting interval (e.g. observational studies, epidemiological studies,
registries, and active surveillance programmes). This should include relevant information from drug
utilisation studies when relevant to multiple regions
The marketing authorisation holder should include an appendix listing marketing authorisation holder-
sponsored non-interventional studies conducted with the primary aim of identifying, characterising or
quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the
effectiveness of risk management measures which were completed or ongoing during the reporting
interval. (see VII.B.5.7. for the information that should be included in the listing).
Final study reports completed during the reporting interval for the studies mentioned in the paragraph
above should also be included in the regional appendix of the PSUR (see VII.B.5.20. and VII.C.5.4.).
Summary information based on aggregate evaluation of data generated from patient support programs
may be included in this section when not presented elsewhere in the PSUR. As for other information
sources, the marketing authorisation holder should present signals or risks identified from such
information in the relevant sections of the PSUR.
VII.B.5.9. PSUR section “Information from other clinical trials and sources”
VII.B.5.9 1. PSUR sub-section “Other clinical trials”
This PSUR sub-section should summarise information relevant to the benefit-risk assessment of the
medicinal product from other clinical trial/study sources which are accessible by the marketing
authorisation holder during the reporting interval (e.g. results from pool analysis or meta-analysis of
randomised clinical trials, safety information provided by co-development partners or from
investigator-initiated trials).
VII.B.5.9 2. PSUR sub-section “Medication errors”
This sub-section should summarise relevant information on patterns of medication errors and potential
medication errors, even when not associated with adverse outcomes. A potential medication error is
the recognition of circumstances that could lead to a medication error, and may or may not involve a
patient. Such information may be relevant to the interpretation of safety data or the overall benefit-
risk evaluation of the medicinal product. A medication error may arise at any stage in the medication
use process and may involve patients, consumers, or healthcare professionals.
VII.B.5.10. PSUR section “Non-clinical data”
This PSUR section should summarise major safety findings from non-clinical in vivo and in vitro studies
(e.g. carcinogenicity, reproduction or immunotoxicity studies) ongoing or completed during the
reporting interval. Results from studies designated to address specific safety concerns should be
included in the PSUR, regardless of the outcome. Implications of these findings should be discussed in
the relevant evaluation sections of the PSUR.
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VII.B.5.11. PSUR section “Literature”
This PSUR section should include a summary of new and significant safety findings, either published in
the peer-reviewed scientific literature or made available as unpublished manuscripts that the
marketing authorisation holder became aware of during the reporting interval, when relevant to the
medicinal product.
Literature searches for PSURs should be wider than those for individual adverse reaction cases as they
should also include studies reporting safety outcomes in groups of subjects and other products
containing the same active substance.
The special types of safety information that should be included, but which may not be found by a
search constructed specifically to identify individual cases, include:
• pregnancy outcomes (including termination) with no adverse outcomes;
• use in paediatric populations;
• compassionate supply, named patient use;
• lack of efficacy;
• asymptomatic overdose, abuse or misuse;
• medication error where no adverse events occurred;
• important non-clinical safety results.
If relevant and applicable, information on other active substances of the same class should be
considered.
The publication reference should be provided in the style of the Vancouver Convention14,15.
VII.B.5.12. PSUR section “Other periodic reports”
This PSUR section will only apply in certain circumstances concerning fixed combination products or
products with multiple indications and/or formulations where multiple PSURs are prepared in
agreement with the competent authority. In general, the marketing authorisation holder should
prepare a single PSUR for a single active substance (unless otherwise specified by the competent
authority); however if multiple PSURs are prepared for a single medicinal product, this section should
also summarise significant findings from other PSURs if they are not presented elsewhere within the
report.
When available, based on the contractual agreements, the marketing authorisation holder should
summarise significant findings from periodic reports provided during the reporting interval by other
parties (e.g. sponsors, other marketing authorisation holders or other contractual partners).
VII.B.5.13. PSUR section “Lack of efficacy in controlled clinical trials”
This section should summarise data from clinical trials indicating lack of efficacy, or lack of efficacy
relative to established therapy(ies), for products intended to treat or prevent serious or life-threatening
14 Uniform requirements for manuscripts submitted to biomedical journals. International Committee of Medical Journal
Editors. N Engl J Med. 1997 Jan 23;336(4):309-15. Available online:
http://www.nejm.org/doi/full/10.1056/NEJM199701233360422
15Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication
[Updated April 2010] Publication Ethics: Sponsorship, Authorship, and Accountability, International Committee of Medical
Journal Editors. http://www.icmje.org/urm_full.pdf
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http://www.nejm.org/doi/full/10.1056/NEJM199701233360422
http://www.icmje.org/urm_full.pdf
illnesses (e.g. excess cardiovascular adverse events in a trial of a new anti-platelet medicine for acute
coronary syndromes) that could reflect a significant risk to the treated population.
VII.B.5.14. PSUR section “Late-breaking information”
The marketing authorisation holder should summarise in this PSUR section the potentially important
safety, efficacy and effectiveness findings that arise after the data lock point but during the period of
preparation of the PSUR. Examples include clinically significant new publications, important follow-up
data, clinically relevant toxicological findings and any action that the marketing authorisation holder, a
data monitoring committee, or a competent authority (worldwide) has taken for safety reasons. New
individual case reports should not be routinely included unless they are considered to constitute an
important index case (i.e. the first instance of an important event) or an important safety signal or
where they may add information to the evaluation of safety concerns already presented in the PSUR
(e.g. a well documented case of aplastic anaemia in a medicinal product known to be associated with
adverse effects on the bone marrow in the absence of possible alternative causes).
Any significant change proposed to the reference product information (e.g. new adverse reaction,
warning or contraindication) which has occurred during this period, should also be included in this
section of the PSUR (see VII.B.4.), where feasible.
The data presented in this section should also be taken into account in the evaluation of risks and new
information (see VII.B.5.16.3.).
VII.B.5.15. PSUR section “Overview of signals: new, ongoing, or closed”
The general location for presentation of information on signals and risks within the PSUR is shown in
figure VII.1 (see VII.B.5.21.). The purpose of this section is to provide a high level overview of
signals16 that were closed (i.e. evaluation was completed) during the reporting interval as well as
ongoing signals that were undergoing evaluation at the end of the reporting interval. For the purposes
of the PSUR, a signal should be included once it has undergone the initial screening or clarification
step, and a determination made to conduct further evaluation by the marketing authorisation
holder17.It should be noted that a safety signal is not synonymous with a statistic of disproportionate
reporting for a specific medicine/event combination as a validation step is required. Signals may be
qualitative (e.g., a pivotal individual case safety report, case series) or quantitative (e.g. a
disproportionality score, findings of a clinical trial or epidemiological study). Signals may arise in the
form of an information request or inquiry on a safety issue from a competent authority (worldwide)
(see Module IX).
Decisions regarding the subsequent classification of these signals and the conclusions of the
evaluation, involve medical judgement and scientific interpretation of available data, which is
presented in section 16 (“Signal and risk evaluation”) of the PSUR.
A new signal refers to a signal that has been identified during the reporting interval. Where new
clinically significant information on a previously closed signal becomes available during the reporting
interval of the PSUR, this would also be considered a new signal on the basis that a new aspect of a
previously refuted signal or recognised risk warrants further action to verify. New signals may be
16 “Signal” means information arising from one or multiple sources, including observations and experiments, which suggests
a new potentially causal association, or a new aspect of a known association between an intervention and an event or set of
related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action [IR Art
19(1)].
17 In the EU-regulatory network and for the purpose of the PSUR, the term “signal” in this section corresponds with the
term “validated signal” described in GVP Module IX.
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classified as closed or ongoing, depending on the status of signal evaluation at the end of the reporting
interval of the PSUR.
Examples of new signals would therefore include new information on a previously:
• Close and refuted signal, which would result in the signal being re-opened.
• Identified risk where the new information suggests a clinically significant difference in the severity
or frequency of the risk (e.g. transient liver enzyme increases are identified risks and new
information indicative of a more severe outcome such as hepatic failure is received, or neutropenia
is an identified risk and a well documented case report of agranulocytosis with no presence of
possible alternative causes is received).
• Identified risk for which a higher frequency or severity of the risk is newly found (e.g. in an
indicated subpopulation).
• Potential risk which, if confirmed, would warrant a new warning, precaution, a new contraindication
or restriction in indication(s) or population or other risk minimisation activities.
Within this section, or as an appendix the marketing authorisation holder should provide a tabulation of
all signals ongoing or closed at the end of the reporting interval. This tabulation should include the
following information:
• a brief description of the signal;
• date when the marketing authorisation holder became aware of the signal;
• status of the signal at the end of the reporting interval (close or ongoing);
• date when the signal was closed, if applicable;
• source of the signal;
• a brief summary of the key data;
• plans for further evaluation; and
• actions taken or planned.
An example of tabulation of signals can be found in VII. Appendix 2.
The detailed signal assessments for closed signals are not to be included in this section but instead
should be presented in sub-section 16.2 (“Signal evaluation”) of the PSUR.
Evaluation of new information in relation to any previously known identified and potential risks and not
considered to constitute a new signal should be provided in PSUR sub-section 16.3 (“Evaluation of risks
and new information”).
When a competent authority (worldwide) has requested that a specific topic (not considered a signal)
be monitored and reported in a PSUR, the marketing authorisation holder should summarise the result
of the analysis in this section if it is negative. If the specific topic becomes a signal, it should be
included in the signal tabulation and discussed in sub-section 16.2 (“Signal evaluation”).
VII.B.5.16. PSUR section “Signal and risk evaluation”
The purpose of this section of the PSUR is to provide:
• A succinct summary of what is known about important identified and potential risks and missing
information at the beginning of the reporting interval covered by the report (VII.B.5.16.1.).
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• An evaluation of all signals closed during the reporting interval (VII.B.5.16.2.).
• An evaluation of new information with respect to previously recognised identified and potential
risks (VII.B.5.16.3).
• An updated characterisation of important potential and identified risks, where applicable
(VII.B.5.16.4.).
• A summary of the effectiveness of risk minimisation activities in any country or region which may
have utility in other countries or regions (VII.B.5.16.5.).
A flowchart illustrating the mapping of signals and risks to specific sections/sub-sections of the PSUR
can be found in VII.B.5.21..
These evaluation sub-sections should not summarise or duplicate information presented in previous
sections of the PSUR but should rather provide interpretation and critical appraisal of the information,
with a view towards characterising the profile of those risks assessed as important. In addition, as a
general rule, it is not necessary to include individual case narratives in the evaluation sections of the
PSUR but where integral to the scientific analysis of a signal or risk, a clinical evaluation of pivotal or
illustrative cases (e.g. the first case of suspected agranulocytosis with an active substance belonging to
a class known to be associated with this adverse reaction) should be provided (see VII.B.3.).
VII.B.5.16.1. PSUR sub-section “Summary of safety concerns”
The purpose of this sub-section is to provide a summary of important safety concerns at the beginning
of the reporting interval, against which new information and evaluations can be made. For products
with an existing safety specification, this section can be either the same as, or derived from the safety
specification summary18 that is current at the start of the reporting interval of the PSUR. It should
provide the following safety information:
• important identified risks;
• important potential risks; and
• missing information.
The following factors should be considered when determining the importance of each risk:
• medical seriousness of the risk, including the impact on individual patients;
• its frequency, predictability, preventability, and reversibility;
• potential impact on public health (frequency; size of treated population); and
• potential for avoidance of the use of a medicinal product with a preventive benefit due to a
disproportionate public perception of risk (e.g. vaccines).
For products without an existing safety specification, this section should provide information on the
important identified and potential risks and missing information associated with use of the product,
based on pre- and post-authorisation experience. Important identified and potential risks may include,
for example:
• important adverse reactions;
• interactions with other medicinal products;
• interactions with foods and other substances;
18 ICH-E2E – Pharmacovigilance planning (see Annex IV).
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• medication errors;
• effects of occupational exposure; and
• pharmacological class effects.
The summary on missing information should take into account whether there are critical gaps in
knowledge for specific safety issues or populations that use the medicinal product.
VII.B.5.16.2. PSUR sub-section “Signal evaluation”
This sub-section of the PSUR should summarise the results of evaluations of all safety signals (whether
or not classified as important) that were closed during the reporting interval. A safety signal can be
closed either because it is refuted or because it is determined to be a potential or identified risk,
following evaluation. The two main categories to be included in this sub-section are:
1. Those signals that, following evaluation, have been refuted as “false” signals based on medical
judgement and scientific evaluation of the currently available information.
2. Those signals that, following evaluation, have been categorised as either a potential or identified
risk, including lack of efficacy.
For both categories of closed signals, a concise description of each signal evaluation should be included
in order to clearly describe the basis upon which the signal was either refuted or considered to be a
potential or identified risk by the marketing authorisation holder.
It is recommended that the level of detail provided in the description of the signal evaluation should
reflect the medical significance of the signal (e.g. severe, irreversible, lead to increased morbidity or
mortality) and potential public health importance (e.g. wide usage, frequency, significant use outside
the recommendations of the product information) and the extent of the available evidence. Where
multiple evaluations will be included under both categories of closed signals, they can be presented in
the following order:
• Closed and refuted signals.
• Closed signals that are categorised as important potential risks.
• Closed signals that are categorised as important identified risks.
• Closed signals that are potential risks not categorised as important.
• Closed signals that are identified risks not categorised as important.
Where applicable the evaluations of closed signals can be presented by indication or population.
The description(s) of the signal evaluations can be included in this sub-section of the PSUR or in an
appendix. Each evaluation should include the following information as appropriate:
• source or trigger of the signal;
• background relevant to the evaluation;
• method(s) of evaluation, including data sources, search criteria (where applicable, the specific
MedDRA terms (e.g. PTs, HLTs, SOCs, etc.) or Standardised MedDRA Queries (SMQs) that were
reviewed), and analytical approaches;
• results - a summary and critical analysis of the data considered in the signal evaluation; where
integral to the assessment, this may include a description of a case series or an individual case
(e.g. an index case of well documented agranulocytosis or Stevens Johnson Syndrome);
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• discussion;
• conclusion.
Marketing authorisation holder’s evaluations and conclusions for refuted signals should be supported
by data and clearly presented.
VII.B.5.16.3. PSUR sub-section “Evaluation of risks and new information”
This sub-section should provide a critical appraisal of new information relevant to previously
recognised risks that is not already included in sub-section 16.2 (“Signal evaluation”).
New information that constitutes a signal with respect to a previously recognised risk or previously
refuted signal should be presented in the signals tabulation (see VII.B.5.15.) and evaluated in sub-
section 16.2 (“Signal evaluation”), if the signal is also closed during the reporting interval of the PSUR.
Updated information on a previously recognised risk that does not constitute a signal should be
included in this sub-section. Examples includes information that confirms a potential risk as an
identified risk, or information which allows any other further characterisation of a previously recognised
risk.
New information can be organised as follows:
1. New information on important potential risks.
2. New information on important identified risks.
3. New information on other potential risks not categorised as important.
4. New information on other identified risks not categorised as important.
5. Update on missing information.
The focus of the evaluation(s) is on new information which has emerged during the reporting interval
of the PSUR. This should be concise and interpret the impact, if any, on the understanding and
characterisation of the risk. Where applicable, the evaluation will form the basis for an updated
characterisation of important potential and identified risks in sub-section 16.4 (“Characterisation of
risks”) of the report. It is recommended that the level of detail of the evaluation included in this sub-
section should be proportional to the available evidence on the risk and its medical significance and
public health relevance.
The evaluation(s) of the new information and missing information update(s) can be included in this
sub-section of the PSUR, or in an appendix. Each evaluation should include the following information as
appropriate:
• source of the new information;
• background relevant to the evaluation;
• method(s) of evaluation, including data sources, search criteria, and analytical approaches;
• results – a summary and critical analysis of the data considered in the risk evaluation;
• discussion;
• conclusion, including whether or not the evaluation supports an update of the characterisation of
any of the important potential and identified risks in sub-section 16.4 (“Characterisation of risks”)
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Any new information on populations exposed or data generated to address previously missing
information should be critically assessed in this sub-section. Unresolved concerns and uncertainties
should be acknowledged.
VII.B.5.16.4. PSUR sub-section “Characterisation of risks”
This sub-section should characterise important identified and potential risks based on cumulative data
(i.e. not restricted to the reporting interval), and describe missing information.
Depending on the nature of the data source, the characterisation of risk may include, where applicable:
• frequency;
• numbers of cases (numerator) and precision of estimate, taking into account the source of the
data;
• extent of use (denominator) expressed as numbers of patients, patient-time, etc., and precision of
estimate;
• estimate of relative risk and precision of estimate;
• estimate of absolute risk and precision of estimate;
• impact on the individual patient (effects on symptoms, quality or quantity of life);
• public health impact;
• patient characteristics relevant to risk (e.g. patient factors (age, pregnancy/lactation, hepatic/renal
impairment, relevant co-morbidity, disease severity, genetic polymorphism);
• dose, route of administration;
• duration of treatment, risk period;
• preventability (i.e. predictability, ability to monitor for a “sentinel” adverse reaction or laboratory
marker);
• reversibility;
• potential mechanism; and
• strength of evidence and its uncertainties, including analysis of conflicting evidence, if applicable.
When missing information could constitute an important risk, it should be included as a safety concern.
The limitations of the safety database (in terms of number of patients studied, cumulative exposure or
long term use, etc.) should be discussed.
For PSURs for products with several indications, formulations, or routes of administration, where there
may be significant differences in the identified and potential risks, it may be appropriate to present
risks by indication, formulation, or route of administration. Headings that could be considered include:
• risks relating to the active substance;
• risks related to a specific formulation or route of administration (including occupational exposure);
• risks relating to a specific population; and
• risks associated with non-prescription use (for compounds that are available as both prescription
and non-prescription products).
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VII.B.5.16.5. PSUR sub-section: “Effectiveness of risk minimisation (if applicable)”
Risk minimisation activities are public health interventions intended to prevent the occurrence of an
adverse drug reaction(s) associated with the exposure to a medicinal product or to reduce its severity
should it occur. The aim of a risk minimisation activity is to reduce the probability or severity of an
adverse drug reaction. Risk minimisation activities may consist of routine risk minimisation (e.g.
product labelling) or additional risk minimisation activities (e.g. Direct Healthcare Professional
Communication/educational materials).
The PSUR shall contain the results of assessments of the effectiveness of risk minimisation activities
relevant to the risk-benefit assessment [IR Art 34(3)].
Relevant information on the effectiveness and/or limitations of specific risk minimisation activities for
important identified risks that has become available during the reporting interval should be
summarised in this sub-section of the PSUR.
Insights into the effectiveness of risk minimisation activities in any country or region that may have
utility in other countries or regions are of particular interest. Information may be summarised by
region, if applicable and relevant.
When required for reporting in a PSUR, results of evaluations that became available during the
reporting interval, which refer to an individual region should be provided in the PSUR regional appendix
(see VII.B.5.20. and VII.C.5.5.).
VII.B.5.17. PSUR section “Benefit evaluation”
PSUR sub-sections 17.1 (“Important baseline efficacy and effectiveness information”) and 17.2 (“Newly
identified information on efficacy and effectiveness”) provide the baseline and newly identified benefit
information that support the characterisation of benefit described in sub-section 17.3
(“Characterisation of benefits”) that in turn supports the benefit-risk evaluation in section 18
(“Integrated benefit-risk analysis for authorised indications”).
VII.B.5.17.1. PSUR sub-section “Important baseline efficacy and effectiveness information”
This sub-section of the PSUR summarises information on both efficacy and effectiveness of the
medicinal product at the beginning of the reporting interval and provides the basis for the benefit
evaluation. This information should relate to authorised indication(s) of the medicinal product listed in
the reference product information (See VII.B.4.).
For medicinal products with multiple indications, populations, and/or routes of administration, the
benefit should be characterised separately by these factors when relevant.
The level of detail provided in this sub-section should be sufficient to support the characterisation of
benefit in the PSUR sub-section 17.3 (“Characterisation of benefits”) and the benefit-risk assessment
in section 18 (“Integrated benefit-risk analysis for authorised indications”).
VII.B.5.17.2. PSUR sub-section “Newly identified information on efficacy and effectiveness”
For some products, additional information on efficacy or effectiveness in authorised indications may
have become available during the reporting interval. Such information should be presented in this sub-
section of the PSUR. For authorised indications, new information on efficacy and effectiveness under
conditions of actual use should also be described in this sub-section, if available. New information on
efficacy and effectiveness in uses other than the authorised indications should not be included unless
relevant for the benefit-risk evaluation in the authorised indications.
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Information on indications newly authorised during the reporting interval should also be included in
this sub-section. The level of detail provided in this section should be sufficient to support the
characterisation of benefit in sub-section 17.3 (“Characterisation of benefits”) and the benefit-risk
assessment in section 18 (“Integrated benefit-risk analysis for authorised indications”).
In this sub-section, particular attention should be given to vaccines, anti-infective agents or other
medicinal products where changes in the therapeutic environment may impact on
efficacy/effectiveness over time.
VII.B.5.17.3. PSUR sub-section “Characterisation of benefits”
This sub-section provides an integration of the baseline benefit information and the new benefit
information that has become available during the reporting interval, for authorised indications.
The level of detail provided in this sub-section should be sufficient to support the analysis of benefit-
risk in section 18 (“Integrated benefit-risk analysis for authorised indications”).
When there are no new relevant benefit data, this sub-section should provide a characterisation of the
information in sub-section 17.1 (“Important baseline efficacy and effectiveness information”).
When there is new positive benefit information and no significant change in the risk profile in this
reporting interval, the integration of baseline and new information in this sub-section should be
succinct.
This sub-section should provide a concise but critical evaluation of the strengths and limitations of the
evidence on efficacy and effectiveness, considering the following when available:
• a brief description of the strength of evidence of benefit, considering comparator(s), effect size,
statistical rigor, methodological strengths and deficiencies, and consistency of findings across
trials/studies;
• new information that challenges the validity of a surrogate endpoint, if used;
• clinical relevance of the effect size;
• generalisability of treatment response across the indicated patient population (e.g. information that
demonstrates lack of treatment effect in a sub-population);
• adequacy of characterization of dose-response;
• duration of effect;
• comparative efficacy; and
• a determination of the extent to which efficacy findings from clinical trials are generalisable to
patient populations treated in medical practice.
VII.B.5.18. PSUR section “Integrated benefit-risk analysis for authorised
indications”
The marketing authorisation holder should provide in this PSUR section an overall appraisal of the
benefit and risk of the medicinal product as used in clinical practice. Whereas sub-sections 16.4
(“Characterisation of risks”) and 17.3 (“Characterisation of benefits”) present the risks and benefits,
this section should provide a critical analysis and integration of the key information in the previous
sections and should not simply duplicate the benefit and risk characterisation presented in the sub-
sections mentioned above.
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VII.B.5.18.1. PSUR sub-section “Benefit-risk context - medical need and important
alternatives”
This sub-section of the PSUR should provide a brief description of the medical need for the medicinal
product in the authorised indications and summarised alternatives (medical, surgical or other;
including no treatment).
VII.B.5.18.2. PSUR sub-section “Benefit-risk analysis evaluation”
A risk-benefit balance is specific to an indication and population. Therefore, for products authorised for
more than one indication, risk-benefit balances should be evaluated and presented by each indication
individually. If there are important differences in the risk-benefit balance among populations within an
indication, the benefit-risk evaluation should be presented by population, if possible.
The benefit-risk evaluation should be presented and discussed in a way that facilitates the comparison
of benefits and risks and should take into account the following points:
• Whereas previous sections/sub-sections should include all important benefit and risk information,
not all benefits and risks contribute importantly to the overall benefit-risk evaluation, therefore,
the key benefits and risks considered in the evaluation should be specified. The key information
presented in the previous benefit and risk section/sub-sections should be carried forward for
integration in the benefit-risk evaluation.
• Consider the context of use of the medicinal product: the condition to be treated, prevented, or
diagnosed; its severity and seriousness; and the population to be treated (relatively healthy;
chronic illness, rare conditions).
• With respect to the key benefit(s), consider its nature, clinical importance, duration, and
generalisability, as well as evidence of efficacy in non-responders to other therapies and alternative
treatments. Consider the effect size. If there are individual elements of benefit, consider all (e.g.
for therapies for rheumatoid arthritis: reduction of symptoms and inhibition of radiographic
progression of joint damage).
• With respect to risk, consider its clinical importance, (e.g. nature of toxicity, seriousness,
frequency, predictability, preventability, reversibility, impact on patients), and whether it arose
from clinical trials in unauthorised indications or populations, off-label use, or misuse.
• The strengths, weaknesses, and uncertainties of the evidence should be considered when
formulating the benefit-risk evaluation. Describe how uncertainties in the benefits and risks impact
the evaluation. Limitations of the assessment should be discussed.
Provide a clear explanation of the methodology and reasoning used to develop the benefit-risk
evaluation:
• The assumptions, considerations, and judgement or weighting that support the conclusions of the
benefit-risk evaluation should be clear.
• If a formal quantitative or semi-quantitative assessment of benefit-risk is provided, a summary of
the methods should be included.
• Economic considerations (e.g. cost-effectiveness) should not be considered in the benefit-risk
evaluation.
When there is important new information or an ad hoc PSUR has been requested, a detailed benefit-
risk analysis should be presented based on cumulative data. Conversely, where little new information
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has become available during the reporting interval, the primary focus of the benefit-risk evaluation
might consist of an evaluation of updated interval safety data.
VII.B.5.19. PSUR section “Conclusions and actions”
A PSUR should conclude with the implications of any new information that arose during the reporting
interval in terms of the overall evaluation of benefit-risk for each authorised indication, as well as for
relevant subgroups, if appropriate.
Based on the evaluation of the cumulative safety data and the benefit-risk analysis, the marketing
authorisation holder should assess the need for changes to the reference product information and
propose changes as appropriate.
In addition and as applicable, the conclusions should include preliminary proposal(s) to optimise or
further evaluate the risk-benefit balance for further discussion with the relevant competent
authority(ies). This may include proposals for additional risk minimisation activities.
For products with a pharmacovigilance or risk management plan, the proposals should also be
considered for incorporation into the pharmacovigilance plan and/or risk minimisation plan, as
appropriate (see Module V).
Based on the evaluation of the cumulative safety data and the risk-benefit analysis, the marketing
authorisation holder shall draw conclusions in the PSUR as to the need for changes and/or actions,
including implications for the approved summary of product characteristics (SmPC) for the product(s)
for which the PSUR is submitted [IR Art 34(5)].
Proposed changes to the reference product information should be described in this section of the PSUR.
The regional appendix should include proposals for product information (SmPC and package leaflet)
together with information on ongoing changes when applicable.
VII.B.5.20. Appendices to the PSUR
A PSUR should contain the following appendices as appropriate, numbered as follows:
1. Reference information (see VII.B.4.).
2. Cumulative summary tabulations of serious adverse events from clinical trials; and cumulative and
interval summary tabulations of serious and non-serious adverse reactions from post-marketing
data sources.
3. Tabular summary of safety signals (if not included in the body of the report)19.
4. Listing of all the marketing authorisation holder-sponsored interventional and non-interventional
studies with the primary aim of identifying, characterising, or quantifying a safety hazard or
confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk
management measures, in case of non-interventional studies.
5. List of the sources of information used to prepare the PSUR (when desired by the marketing
authorisation holder).
6. Regional appendix:
The requirements for the regional appendix in the EU are provided in section VII.C.5..
19 It is preferred to include the tabulation of signals in the body of the PSUR, if feasible.
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VII.B.5.21. Mapping signals and risks to PSUR sections/sub-sections
The following flowchart (Figure VII.1) reflects the general location for the presentation of information
on signals and risks within the PSUR.
Figure VII.1. PSUR Sections/subsections – signals and risks.
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VII.B.6. Quality systems for PSURs at the level of marketing authorisation
holders
Marketing authorisation holders should have in place structures and processes for the preparation,
quality control, review and submission of PSURs including follow-up during and after their assessment.
These structures and processes should be described by means of written policies and procedures in the
marketing authorisation holder’s quality system (see Module I).
There are a number of areas in the pharmacovigilance process that can directly impact the quality of
PSURs, some examples are case management of spontaneous and study reports, literature screening,
signal management, additional pharmacovigilance and post-marketing research activities, procedures
for integration of information on benefits and risks from all available data sources and maintenance of
product information. The quality system should describe the links between the processes, the
communication channels and the responsibilities with the aim of gathering all the relevant information
for the production of PSURs. There should be documented procedures including quality control checks
in place to check the accuracy and completeness of the data presented in the PSURs. In ensuring
completeness of data, a documented template or plan for drawing data from various data sources
could be developed. The importance of an integrated approach to benefit-risk evaluation should
underpin processes and cross departmental input to PSUR preparation.
The PSUR should also contain the assessment of specific safety issues requested by competent
authorities in accordance with agreed timelines and procedures. The marketing authorisation holder
should have mechanisms in place to ensure that the requests made by competent authorities during
the time of their PSUR assessment are properly addressed.
The provision of the data included in the summary tabulations (see VII.B.5.6.) should undergo source
data verification against the marketing authorisation holder’s safety database to ensure accuracy of the
number of events/reactions provided. The process for querying the safety database, the parameters
used for the retrieval of the data and the quality control performed should be properly documented.
An appropriate quality system should be in place in order to avoid failure to comply with PSUR
requirements such as:
• non-submission: complete non-submission of PSURs, submission outside the correct submission
schedule or outside the correct time frames (without previous agreement with the competent
authorities);
• unjustified omission of information required by VII.B.5.;
• poor quality reports: poor documentation or insufficient information or evaluation provided to
perform a thorough assessment of the new safety information, signals, risk evaluation, benefit
evaluation and integrated benefit-risk analysis, misuse not highlighted, absence of use of
standardised medical terminology (e.g. MedDRA) and inappropriate dismissal of cases with no
reported risk factors in cumulative reviews;
• submission of a PSUR where previous requests from competent authorities have not been
addressed;
• failure to provide an explicit evaluation of the risk-benefit balance of the medicinal product;
• failure to provide adequate proposals for the local authorised product information.
Any significant deviation from the procedures relating to the preparation or submission of PSURs
should be documented and the appropriate corrective and preventive action should be taken. This
documentation should be available at all times.
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When marketing authorisation holders are involved in contractual arrangements (e.g. licensor-
licensee), respective responsibilities for preparation and submission of the PSUR to the competent
authorities should be clearly specified in the written agreement.
When the preparation of the PSUR is delegated to third parties, the marketing authorisation holder
should ensure that they are subject to a quality system compliant with the current legislation. Explicit
procedures and detailed agreements should exist between the marketing authorisation holder and third
parties. The agreements may specifically detail the options to audit the PSUR preparation process.
VII.B.7. Training of staff members related to the PSUR process
For all organisations, it is the responsibility of the person responsible for the pharmacovigilance system
to ensure that the personnel, including pharmacovigilance, medical and quality personnel involved in
the preparation, review, quality control, submission and assessment of PSURs are adequately qualified,
experienced and trained according to the applicable guidelines (e.g. ICH E2C(R2) and this GVP Module
VII). When appropriate, specific training for the different processes, tasks and responsibilities relating
to the PSUR should be in place.
Training to update knowledge and skills should also take place as necessary.
Training should cover legislation, guidelines, scientific evaluation and written procedures related to the
PSUR process. Training records should demonstrate that the relevant training was delivered prior to
performing PSUR-related activities.
VII.C. Operation of the EU network
VII.C.1. PSUR process in the EU - General process
The following flowchart (Figure VII.2.) reflects the general process cycle for the PSUR procedure at the
EU level when recommendations by the PRAC are issued. This represents a high level cycle to outline
the entire process, from the preparation of the report to the implementation of the European
Commission decision/national actions when applicable. Different single steps in this flowchart are
formed by intermediate steps further explained and developed in different sections in this Module.
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Figure VII.2. PSUR procedure - general process
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VII.C.2. Standard submission schedule of PSURs
Marketing authorisation holders for products authorised before 02 July 2012 (centrally authorised
products) and 21 July 2012 (nationally authorised products) and for which the frequency and dates of
submission of PSURs are not laid down as a condition to the marketing authorisation or determined
otherwise in the list of Union reference dates, shall submit PSURs according to the following submission
schedule [REG 28(2), DIR Art 107c(2)].
• at 6 months intervals once the product is authorised, even if it is not marketed;
• once a product is marketed, 6 monthly PSUR submission should be continued following initial
placing on the market in the EU for 2 years, then once a year for the following 2 years and
thereafter at 3-yearly intervals.
VII.C.3. List of European Union reference dates and frequency of
submission of PSURs20
VII.C.3.1. Objectives of the EU reference dates list
The Agency shall make public a list of Union reference dates (hereinafter referred to as list of EU
reference dates) and frequency of submission of PSURs by means of the European medicines web-
portal [DIR Art 107c(7), REG Art 26(1)(g)].
The objectives of the list of EU reference dates and frequency of submission of PSURs are:
• Harmonisation of data lock point and frequency of submission of PSURs for the same active
substance and combination of active substances:
For medicinal products containing the same active substance or combination of active substances
subject to different marketing authorisations, an EU reference date should be set up and the
frequency and date of submission of PSURs harmonised in order to allow the preparation of a
single assessment established in DIR Art 107e(1). Such information should be included in the list
published by the Agency.
• Optimisation of the management of PSURs and PSURs assessments within the EU:
The list overrules the submission schedule described in DIR Art 107c(2)(b).
For active substances or combinations of active substances included in the list, marketing
authorisation holders shall vary, if applicable, the condition laid down in their marketing
authorisations in order to allow the submission of PSURs in accordance to the frequency and
submission date as indicated in the list [DIR 107c(4) to (7)].
The periodicity is defined on the basis of a risk-based approach in order to prioritise the periodic
re-evaluation of the risk-benefit balance of active substances in a way that best protects public
health [Directive 2010/84/EU Preamble Recital 23].
• Single EU assessment and reassessment of the risk-benefit balance of an active substance based
on all available safety data:
The list enables the harmonisation of PSUR submissions for medicinal products containing the
same active substance or the same combination of active substances.
20 The initial EU reference dates list was adopted by the CHMP/CMDh following consultation of the PRAC in September 2012
and was published on 01 October 2012.
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A single EU PSUR assessment provides a mechanism for evaluating the totality of available data on
the benefits and risks of an active substance or combination of active substances. The effective
application of work sharing principles is important in avoiding duplication of efforts and in
prioritising the use of limited resources in the best interests of European citizens.
VII.C.3.2. Description of the EU reference dates list
The Union reference date of medicinal products containing the same active substance or the same
combination of active substances shall be [DIR Art 107c(5)]:
• the date of the first marketing authorisation in the EU of a medicinal product containing that active
substance or that combination of active substances; or
• if the date of first marketing authorisation cannot be ascertained, the earliest of the known dates
of the marketing authorisations for a medicinal product containing that active substance or that
combination of active substances.
The list of EU reference dates and frequency of submission of PSURs consists of a comprehensive list of
substances and combinations of active substances in alphabetical order, for which PSURs, where
required, shall be submitted in accordance with the EU reference date and the frequency as
determined by the Committee for Medicinal Products for Human Use (CHMP) and the Coordination
Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) following consultation
with the Pharmacovigilance Risk Assessment Committee (PRAC) [DIR Art 107c(4) and (6)]. The list
should be updated in line with the “list of all medicinal products for human use authorised in the Union”
as referred to in REG Art 57(1)(b).
The EU reference dates list should contain the following information:
• the EU reference dates;
• the frequencies of submission of PSURs;
• the data lock points of the next submissions of PSURs;
• the date of publication (on the European Medicines web-portal) of the frequency for PSURs
submission and data lock point for each active substance and combination of active substances.
Any change to the dates of submission and frequency on PSURs specified in the marketing
authorisation shall take effect 6 months after the date of such publication [DIR Art 107c(7)].
Where specificity is deemed necessary, the list should include the scope of the PSUR and related EU
single assessment procedure (see VII.C.3.3.) such as:
• whether or not it should cover all the indications of the substance or combination of active
substances;
• whether or not it should cover all the formulations/routes of administration of the products
containing a substance or combination of active substances;
• whether generic, well-established use, traditional herbal and homeopathic medicinal products shall
submit a PSUR due to a request from a competent authority or due to concerns relating to
pharmacovigilance data or due to the lack of PSURs relating to an active substance after the
marketing authorisation has been granted [DIR Art 107c(2) second subparagraph] (see
VII.C.3.3.2.).
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VII.C.3.3. Application of the list of EU reference dates to submission of
PSURs
VII.C.3.3.1. Submission of PSURs for medicinal products: general requirement
Figure VII.3. presents the various potential scenarios for the submission of a PSUR as a general
requirement.
Figure VII.3. Conditions for PSURs submission as general requirement
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The data lock points included in the list of EU references dates enable the synchronisation of PSURs
submission for products subject to different marketing authorisations and permit the EU single
assessment. These data lock points are fixed on a certain date of the month, and should be used to
determine the submission date (which has legal status) of the PSUR. Marketing authorisation holders
can request to amend those dates in accordance with section VII.C.3.5.2.
Unless otherwise specified in the list of EU reference dates and frequency of submission, or agreed with
competent authorities in Member States or the Agency, as appropriate, a single PSUR shall be
prepared for all medicinal products containing the same active substance and authorised for one
marketing authorisation holder. The PSUR shall cover all indications, routes of administration, dosage
forms and dosing regimens, irrespective of whether authorised under different names and through
separate procedures. Where relevant, data relating to a particular indication, dosage form, route of
administration or dosing regimen shall be presented in a separate section of the PSUR and any safety
concerns shall be addressed accordingly [IR Art 34(6)].
For medicinal products containing an active substance or a combination of active substances not
included in the EU reference dates list, PSURs shall be submitted according to the PSUR frequency
defined in the marketing authorisation or if not specified, in accordance with the submission schedule
specified in DIR Art 107c(2) and REG Art 28(2).
VII.C.3.3.2. Submission of PSURs for generic, well-established use, traditional herbal and
homeopathic medicinal products
By way of derogation, generics (authorised under DIR Art 10(1)), well-established use (authorised
under DIR Art 10a), homeopathic (authorised under DIR Art 14) and traditional herbal (authorised
under DIR Art 16a) medicinal products are exempted from submitting PSURs except in the following
circumstances [DIR Art 107b(3)]:
• the marketing authorisation provides for the submission of PSURs as a condition;
• PSURs is (are) requested by a competent authority in a Member State on the basis of concerns
relating to pharmacovigilance data or due to the lack of PSURs relating to an active substance after
the marketing authorisation has been granted (e.g. when the “reference” medicinal product is no
longer marketed). The assessment reports of the requested PSURs shall be communicated to the
PRAC, which shall consider whether there is a need for a single assessment report for all marketing
authorisations for medicinal products containing the same active substance and inform the CMDh
or CHMP accordingly, in order to apply the procedures laid down in DIR Art 107c(4) and 107e.
In order to facilitate and optimise the PSUR EU single assessment process, to avoid duplications of
requests for PSURs and to provide transparency and predictability for the marketing authorisation
holders, the legislative provision laid down in DIR 107b(3)(b) is applied by specifying in the list of EU
reference dates, the substances for which PSURs for generic, well-established use, traditional herbal
and homeopathic medicinal products are required. This specification is based on the request made by a
competent authority in a Member State during the creation or maintenance of the list of EU reference
dates and on the basis of concerns relating to pharmacovigilance data or due to the lack of PSURs
relating to an active substance.
The harmonised frequency for the submission of the reports and the EU reference dates are
determined by the CHMP and/or CMDh after consultation of the PRAC.
The application of the list of EU reference dates for the submission of PSURs for generic, well-
established use, traditional herbal and homeopathic medicinal products does not undermine the right
of a competent authority in a Member State to request the submission of PSURs at any time under the
provision laid down in [DIR Art 107c(2) second subparagraph].
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For products where PSURs are no longer required to be submitted routinely, it is expected that
marketing authorisation holders will continue to evaluate the safety of their products on a regular basis
and report any new safety information that impacts on the risk-benefit balance or the product
information (See Module VI and Module IX).
Figure VII.4. presents the various potential scenarios as regard the submission of a PSUR for generic,
well-established use, traditional herbal and homeopathic medicinal products:
Figure VII.4. Conditions for PSURs submission for generic, well-established use, traditional herbal
and homeopathic medicinal products.
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VII.C.3.3.3. Submission of PSURs for fixed dose combination products
Unless otherwise specified in the list of EU reference dates and frequency of submission, if the
substance that is the subject of the PSUR is also authorised as a component of a fixed combination
medicinal product, the marketing authorisation holder shall either submit a separate PSUR for the
combination of active substances authorised for the same marketing authorisation holder with cross-
references to the single-substance PSUR(s), or provide the combination data within one of the single-
substance PSURs [IR Art 34(7)].
VII.C.3.3.4. Submission of PSURs on demand of a competent authority in a Member State
Marketing authorisation holders shall submit PSURs immediately upon request from a competent
authority in a Member State [DIR Art 107c(2)]. To facilitate the EU assessment and avoid duplication
of requests, the competent authorities in the Member States should normally make use of the list of EU
reference dates to request the submission of PSURs, however in especial circumstances competent
authorities in Member States can directly request the submission of a PSUR. When the timeline for
submission has not been specified in the request, marketing authorisation holders should submit the
PSUR within 90 calendar days of the data lock point.
VII.C.3.4. Criteria used for defining the frequency of submission of PSURs
When deviating from the PSUR submission schedule defined in DIR Art 107c(2)(b), the frequencies of
submission of PSURs and the corresponding data lock points should be defined on a risk-based
approach by the CHMP where at least one of the marketing authorisations concerned has been granted
in accordance with the centralised procedure or by the CMDh otherwise, after consultation with the
PRAC.
The following prioritisation criteria should be taken into account when defining the frequency of
submission for a given active substance or combination of active substances:
• information on risks or benefits that may have an impact on the public health;
• new product for which there is limited safety information available to date (includes pre- and post-
authorisation experiences);
• significant changes to the product (e.g. new indication has been authorised, new pharmaceutical
form or route of administration broadening the exposed patient population);
• vulnerable patient populations/poorly studied patient populations, missing information (e.g.
children, pregnant women) while these populations are likely to be exposed in the post-
authorisation setting;
• signal of/potential for misuse, medication error, risk of overdose or dependency;
• the size of the safety database and exposure to the medicinal product;
• medicinal products subjected to additional monitoring.
Any change in the criteria listed above for a given active substance or combination of active substances
may lead to an amendment of the list of EU reference dates (e.g. increase of the frequency for PSUR
submission).
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VII.C.3.5. Maintenance of the list of EU reference dates
VII.C.3.5.1. General principles
The maintenance of the list of EU reference dates should facilitate regulatory responsiveness to public
health concerns identified within the EU and therefore the list will be subject to changes to reflect the
decisions taken (e.g. by the Agency’s committees following signal detection).
The information included in the list such as the active substances and combinations of active
substances, the frequencies of submission of PSURs and data lock points may need to be updated
when considered necessary by the CHMP or CMDh after consultation with the PRAC. Changes to the list
may be applied on one of the following grounds:
• emergence of new information that might have an impact on the risk-benefit balance of the active
substances or combinations of active substances, and potentially on public health;
• any change in the criteria used for the allocation of frequency for PSUR submission and defined
under VII.C.3.4.;
• a request from the marketing authorisation holders as defined under DIR Art 107c(6);
• active substance newly authorised.
Figure VII.5. provides a general overview of the maintenance of the list of EU reference dates and
frequency of submission of PSURs:
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Figure VII.5. Maintenance of the list of EU reference dates and frequency of submission of PSURs
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VII.C.3.5.2. Requests from marketing authorisation holders to amend the list of EU
reference dates
Marketing authorisation holders shall be allowed to submit a request to the CHMP or the CMDh, as
appropriate, to determine the Union reference dates or to change the frequency of submission of
PSURs on one of the following grounds [DIR Art 107c(6)]:
• for reasons relating to public health;
• in order to avoid a duplication of the assessment;
• in order to achieve international harmonisation.
The request and its grounds should be considered by the PRAC and the CHMP if it concerns at least one
marketing authorisation granted in accordance with the centralised procedure or the CMDh otherwise,
which will either approve or deny the request.
The list will then be amended accordingly when appropriate and published on the European medicines
web-portal (see section VII.C.3.6.).
For details about how to submit requests for amendments to the list, refer to the EU reference dates
cover note and the related template published on the European medicines web-portal21
VII.C.3.6. Publication of the list
Upon its establishment and adoption by the CHMP and CMDh following PRAC consultation, the list of EU
reference dates and frequency of submission of PSURs is published on the European medicines web-
portal.
In case of amendments, the updated list should be published following its adoption by the CHMP or the
CMDh. It is expected to be updated monthly.
VII.C.3.7. Amendment of the marketing authorisation according to the list
of EU reference dates
Any changes to the dates and frequencies of submission of PSURs specified in the list take effect six
months after the date of the publication on the European medicines web-portal. Where appropriate,
marketing authorisation holders shall submit the relevant variation in order to reflect the changes in
their marketing authorisation [DIR 107c(6)], unless the marketing authorisation contains a direct cross
reference to the list of EU references dates.
VII.C.4. Processes for PSUR Assessment in the EU network
The competent authorities in the Member States shall assess PSURs to determine whether there are
new risks or whether risks have changed or whether there are changes to the risk-benefit balance of
the medicinal product [DIR Art 107d].
For purely nationally authorised medicinal products authorised in one Member State, the assessment of
PSURs is conducted by the competent authority in the Member State where the product is authorised
(see VII.C.4.1.).
For medicinal products authorised in more than one Member State, containing the same active
substance or the same combination of active substances whether or not held by the same marketing
authorisation holders and for which the frequency and dates of submission of PSURs have been
21 http://www.emea.europa.eu
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harmonised in the list of EU reference dates, an EU single assessment of all PSURs is conducted with
recommendation from the PRAC in accordance with the procedure described in VII.C.4.2.1. and
VII.C.4.2.2..
Further to assessment of the PSUR and opinion from the CHMP or position from the CMDh, as
applicable, following the recommendation from the PRAC, the competent authorities in Member States,
or the European Commission for centrally authorised products, shall take the necessary measures to
vary, suspend or revoke the marketing authorisation(s), in accordance with outcome of the
assessment [DIR Art 107g(2)] [REG Art 28(4) and (5)] (see VII.C.4.2.3. and VII.C.4.2.4.).
The outcome of the PSUR assessment results in a legally binding decision or position in case of any
action to vary, suspend, revoke the marketing authorisations of the medicinal products containing the
concerned active substance or combination of active substances, on the basis of the position of the
CMDh or the opinion of the CHMP following the recommendations from the PRAC. Furthermore,
marketing authorisation holders are reminded of their obligation to keep their marketing authorisation
up to date in accordance with REG Art 16(3) and DIR Art 23(3). The recommendations are therefore
implemented in a harmonised and timely manner for all products within the scope of the procedure
across the EU.
Amendments to the SmPC, package leaflet and labelling as a result of the PSUR assessment should be
implemented without subsequent variation submission for centrally authorised products and through
the appropriate variation for nationally authorised products, including those authorised through the
mutual recognition and decentralised procedures.
When the proposals for the product information include new adverse reactions in section 4.8
(“Undesirable effects”) of the SmPC, or modifications in the description, frequency and severity of the
existing reactions, marketing authorisation holders should provide in the relevant sections of the PSUR
appropriate information to allow the adequate description and classification of the frequency of the
adverse reactions. If other sections of the SmPC (e.g. SmPC section 4.4 “Special warnings and
precautions for use”) are considered to be updated, clear proposals should be provided for the
competent authorities in the Member States to consider during the PSUR assessment22. The proposals
should be included in the PSUR regional appendix (VII.C.5.).
Harmonisation of the entire product information in all the Member States where the product is
authorised is not one of the objectives of the PSUR assessment procedure. Instead, the outcome of the
assessment should incorporate the new safety warnings and key risk minimisation recommendations,
arising from the assessment of the data in the PSUR, to be included in the relevant sections of the
product information.
VII.C.4.1. PSURs for purely nationally authorised medicinal products
It is the responsibility of the competent authority in the Member State where the product is authorised
to evaluate the PSURs for these medicinal products and the assessment is conducted in accordance
with the national legislation.
Listings of individual cases may be requested in the context of the PSUR assessment procedure for
adverse reactions of special interest and should be provided by the marketing authorisation holder
within an established timeframe to be included in the request. This may be accompanied by a request
for an analysis of individual case safety reports, (including information on numbers of cases, details of
fatal cases and as necessary, analysis of non-serious cases), where necessary for the scientific
evaluation. Information on the context or rationale for the request should generally be provided.
22 See “Guideline on Summary of Product Characteristics” as published on the Website of the European Commission in the
Notice to Applicants, Volume 2C: http://ec.europa.eu/health/files/eudralex
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Following the assessment of PSURs, the competent authority in the Member State should consider
whether any action concerning the marketing authorisation for the medicinal product concerned is
necessary. They should vary, suspend or revoke the marketing authorisation when applicable
according to the appropriate procedure at national level.
The assessment report and conclusions of the competent authority in the Member State should be
provided to the marketing authorisation holder.
VII.C.4.2. Medicinal products authorised in more than one Member State
VII.C.4.2.1. Assessment of PSURs for a single centrally authorised medicinal product
This section describes the assessment of PSURs where only one centrally authorised medicinal product
is involved according to the procedure set up in Article 28 of Regulation (EC) No 726/2004 (see figure
VII.6.).
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Figure VII.6. PSUR assessment procedure for a single centrally authorised medicinal product
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The assessment of PSURs for a single centrally authorised medicinal product is coordinated by the
Agency and shall be conducted by a Rapporteur appointed by the PRAC [REG Art 28(3)] (hereinafter
referred to as “PRAC Rapporteur”).
Upon receipt, the Agency should perform a technical validation of the report to ensure that the PSUR
application is in a suitable format.
Listings of individual cases from EudraVigilance database may be retrieved to support the PSUR
assessment.
Further to the above verifications, the procedure starts in accordance with the official starting dates
published on the Agency's website. The detailed procedural timetables are published as a generic
calendar on the Agency's website.
The published timetables identify the submission, start and finish dates of the procedures as well as
other interim dates/milestones that occur during the procedure.
During the assessment, additional listings of individual cases may be requested by the PRAC
Rapporteur through the Agency for adverse reactions of special interest and should be provided by the
marketing authorisation holder(s) within an established timeframe to be included in the request. This
may be accompanied by a request for an analysis of individual cases safety reports, (including
information on numbers of cases, details of fatal cases and as necessary, analysis of non-serious
cases), where necessary for the scientific evaluation. Information on the context or rationale for the
request should generally be provided.
During the drafting of the assessment report, the PRAC Rapporteur shall closely collaborate with the
CHMP Rapporteur [REG Art 28(3)].
The PRAC Rapporteur shall prepare an assessment report and send it to the Agency and to the
members of the PRAC [REG Art 28(3)] within 60 days of the start of the procedure.
The Agency shall send the PRAC Rapporteur’s preliminary assessment report to the marketing
authorisation holder [REG Art 28(3)].
By Day 90, the marketing authorisation holder and members of the PRAC may send comments on the
PRAC Rapporteur’s preliminary assessment report to the Agency and the PRAC Rapporteur. Those
comments should also include responses to outstanding issues or questions raised by the PRAC
Rapporteur in the preliminary assessment report and which can be addressed within the timeframe of
the comments phase.
Following receipt of comments, the PRAC Rapporteur shall prepare an updated assessment report [REG
Art 28(3)] within 15 days (i.e. by Day 105). The updated assessment report is made available to the
members of the PRAC and should be forwarded to the marketing authorisation holder by the Agency
An oral explanation to the PRAC can be held at the request of the PRAC or the marketing authorisation
holder in case of recommendation for a revocation or suspension of the marketing authorisation, a new
contraindication, a restriction of the indication or a reduction of the recommended dose.
The PRAC shall adopt the updated assessment report with or without further changes at its next
meeting [REG Art 28(3)], together with a recommendation on the maintenance of the marketing
authorisation or the need to vary, suspend or revoke the marketing authorisation. The PRAC
recommendation may also highlight the need to conduct a post-authorisation safety study, request an
update of the RMP, review of safety issues and/or close monitoring of events of interest.
Divergent positions of PRAC members and the grounds on which they are based shall be reflected in
the recommendation issued by the PRAC [REG Art 28(3)].
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The Agency shall include the PRAC recommendation and adopted assessment report in the repository,
and forward both to the marketing authorisation holder [REG Art 28(3)].
Further to adoption at the PRAC meeting, in case of any regulatory action is recommended, the
assessment report and PRAC recommendation are sent to the CHMP for adoption of an opinion for the
centrally authorised product concerned as described in VII.C.4.2.3..
VII.C.4.2.2. Assessment of PSURs for medicinal products subject to different marketing
authorisations containing the same active substance (EU single assessment)
This section describes the assessment of PSURs for medicinal products subject to different marketing
authorisations, authorised in more than one Member State, containing the same active substance or
the same combination of active substances whether or not held by the same marketing authorisation
holder and for which the frequency and dates of submission of PSURs have been harmonised in the list
of EU reference dates. This could include a mixture of centrally authorised products, products
authorised through the mutual recognition, decentralised and national procedures. [DIR Art 107e to
107g] (so-called PSUR “EU single assessment” procedure).
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Figure VII.7. PSUR assessment procedure for “EU single assessment”
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The assessment of PSURs for medicinal products, also called “EU single assessment”, shall be
conducted by [DIR Art 107e(1)]:
• a “Member State” appointed by the CMDh where none of the marketing authorisations concerned
has been granted in accordance with the centralised procedure;
• a “Rapporteur” appointed by the PRAC, where at least one of the marketing authorisations
concerned has been granted in accordance with the centralised procedure (hereinafter referred to
as “PRAC Rapporteur”).
The PSUR EU single assessment procedure is coordinated by the Agency. Upon receipt, the Agency
should perform a technical validation of the reports to ensure that the PSURs applications are in a
suitable format.
Upon establishment of the list of all medicinal products for human use authorised in the EU referred to
in REG Art 57, the Agency should ensure that all marketing authorisation holder(s) of the given
substance have submitted PSUR(s), as required. In the event where a PSUR has not been submitted,
the Agency should contact the concerned marketing authorisation holder(s). However, this will not
preclude the start of the single assessment procedure for other PSUR(s) of the same active substance.
Listings of individual cases from EudraVigilance database may be retrieved to support the PSURs
assessment.
Further to the above verifications, the procedure starts in accordance with the official starting dates
published on the Agency's website. The detailed procedural timetables are published as a generic
calendar on the Agency's website.
The published timetables identify the submission, start and finish dates of the procedures as well as
other interim dates/milestones that occur during the procedure.
Further to the start of procedure, the PRAC Rapporteur or Member State conducts the single
assessment of all PSURs submitted for the given active substance.
During the assessment, additional listings of individual cases may be requested by the PRAC
Rapporteur or Member State through the Agency for adverse drug reactions of special interest and
should be provided by the marketing authorisation holder(s) within an established timeframe to be
included in the request. This may be accompanied by a request for an analysis of individual cases
safety reports, (including information on numbers of cases, details of fatal cases and as necessary,
analysis of non-serious cases), where necessary for the scientific evaluation. Information on the
context or rationale for the request should generally be provided.
The PRAC Rapporteur or Member State shall prepare an assessment report and send it to the Agency
and to the Member States concerned [DIR Art 107e(2)] within 60 days of the start of the procedure.
This preliminary assessment report should be circulated to the members of the PRAC.
The Agency shall send the PRAC Rapporteur’s/Member State preliminary assessment report to the
concerned marketing authorisation holder(s) [DIR Art 107e(2)]. This assessment report should be
circulated amongst all the marketing authorisation holders whose medicinal product(s) are part of the
EU single assessment.
By Day 90, the marketing authorisation holder(s), Member States and members of the PRAC as
applicable may send comments on the PRAC Rapporteur’s/Member State’s preliminary assessment
report to the Agency and the PRAC Rapporteur/Member State, as applicable. Those comments should
also include responses to outstanding issues or questions raised by the PRAC Rapporteur/Member
State in the preliminary assessment report and which can be addressed within the timeframe of the
comments phase.
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Following receipt of comments, the PRAC Rapporteur/Member State shall prepare an updated
assessment report [DIR Art 107e (3)] within 15 days (i.e. by Day 105). The updated assessment
report is forwarded to the members of the PRAC and should be circulated by the Agency amongst all
the marketing authorisation holders whose medicinal product(s) are part of the EU single assessment.
An oral explanation to the PRAC can be held at the request of the PRAC or the marketing authorisation
holder in case of recommendation for a revocation or suspension of the marketing authorisation, a new
contraindication, a restriction of the indication or a reduction of the recommended dose.
The PRAC shall adopt the updated assessment report with or without further changes at its next
meeting [DIR Art 107e(3)], together with a recommendation on maintenance of the marketing
authorisation or the need to vary, suspend or revoke the marketing authorisation. The PRAC
recommendation may also highlight the need to conduct a post-authorisation safety study (see Module
VIII), request an update of the RMP (see Module V), review of safety issue and/or close monitoring of
events of interest.
Divergent positions of PRAC members and the grounds on which they are based shall be reflected in
the recommendation issued by the PRAC [DIR Art 107e(3)].
The Agency shall include the PRAC recommendation and adopted assessment report in the repository,
and forward both to the marketing authorisation holder(s) [DIR Art 107e(3)].
Further to adoption at the PRAC meeting, in case of any regulatory action is recommended, the
assessment report and PRAC recommendation are sent to:
• the CHMP where at least one centrally authorised product is included in the single assessment, for
adoption of an opinion as described in VII.C.4.2.3.;
• the CMDh where no centrally authorised product is included in the single assessment, for
agreement of a position as described in VII.C.4.2.4..
VII.C.4.2.3. Single assessment including at least one centrally authorised product leading to
a CHMP opinion
The CHMP acknowledges receipt of the PRAC recommendation and assessment report, in case of any
regulatory action, at their next meeting following the PRAC adoption. Within 30 days from receipt, the
CHMP shall consider the PRAC assessment report and recommendation and adopt an opinion on the
maintenance, variation, suspension, revocation of the marketing authorisation(s) concerned [DIR
107g(3)].
An oral explanation to the CHMP can be held at the request of the CHMP or the marketing authorisation
holder(s) only in case of differences with the PRAC recommendation where CHMP considers the
possibility of adopting an opinion on the suspension or revocation of the marketing authorisation(s), a
new contraindication, a restriction of the indication or a reduction of the recommended dose.
The opinion will contain the following:
• the final assessment report and recommendation adopted by the PRAC;
• detailed explanation of the scientific grounds for differences with the PRAC recommendation, if
applicable [DIR Art 107g(3)];
• in the case of a CHMP opinion to vary the marketing authorisation(s):
− the scientific conclusions and grounds recommending the variation to the terms of the
marketing authorisation;
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− for centrally authorised products, revised product information and if applicable, conditions
imposed to the marketing authorisation holder and where appropriate, the conditions or
restrictions imposed to the Member States for the safe and effective used of the medicinal
product, in accordance with the provision provided in DIR Art 127a;
− for nationally authorised products, including those authorised through the mutual recognition
and decentralised procedures, an annex indicating the new safety warnings and key risk
minimisation recommendations to be included in the relevant sections of the product
information as applicable.
• in the case of a CHMP opinion to suspend the marketing authorisation(s), the scientific conclusions
together with the grounds for suspension and conditions for lifting the suspension;
• in the case of a CHMP opinion to revoke the marketing authorisation(s), the scientific conclusions
together with the grounds for revocation;
• divergent positions of CHMP members, where applicable.
Further to adoption, the Agency should send the CHMP opinion together with its annexes and
appendices to the European Commission, marketing authorisation holder(s) and competent authorities
in Member States.
The final assessment conclusions and recommendations are published in the European medicines web-
portal (VII.C.7.).
a. Post CHMP opinion - Centrally authorised products
Where the CHMP opinion states that the terms of the marketing authorisation(s) needs to be varied,
the marketing authorisation holder(s) of centrally authorised products should provide the translations
of the product information and the scientific conclusions and grounds recommending the variation to
the terms of the marketing authorisation, in all EU official languages, in accordance with the translation
timetable adopted by the CHMP.
Further to receipt of a CHMP opinion stating that regulatory action to the concerned marketing
authorisation is necessary, the European Commission shall adopt a decision addressed to marketing
authorisation holders to vary, suspend or revoke the marketing authorisation(s) of centrally authorised
product(s) [DIR Art 107g(4b)].
Further to adoption, the European Commission should notify the decisions amending the terms of the
marketing authorisation of centrally authorised products to the marketing authorisation holder(s).
b. Post CHMP opinion - Nationally authorised products, including those authorised through
the mutual recognition and decentralised procedures
Further to receipt of a CHMP opinion stating that regulatory action to the concerned marketing
authorisations is necessary, the European Commission shall adopt a decision addressed to the
competent authorities in Member States concerning the measures to be taken [DIR Art 107g(a)] in
respect of nationally authorised products, including those authorised through the mutual recognition
and decentralised procedures.
Further to the receipt of the decision from the European Commission, the competent authorities in
Member States shall take the necessary measures to vary, suspend or revoke the marketing
authorisation(s) within 30 days [DIR Art 107g(4)].
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VII.C.4.2.4. Single assessment not including centrally authorised product leading to a CMDh
position
The CMDh acknowledges receipt of the PRAC recommendation and assessment report, in case of any
regulatory action, at their next meeting following the PRAC adoption.
Within 30 days from receipt, the CMDh shall consider the PRAC assessment report and
recommendation and reach a position on the maintenance, variation, suspension, revocation of the
marketing authorisation(s) concerned [DIR Art 107g(1)].
An oral explanation to the CMDh can be held at the request of the CMDh or the marketing
authorisation holder(s), only in case of differences with the PRAC recommendation where the CMDh
considers the possibility to reach a position on the suspension or revocation of the marketing
authorisation(s), a new contraindication, a restriction of the indication or a reduction of the
recommended dose.
The position will contain the following:
• the final assessment report and recommendation adopted by the PRAC;
• detailed explanation of the scientific grounds for differences with the PRAC recommendation, if
applicable [DIR Art 107g(2)];
• in the case of a CMDh position to vary the marketing authorisation(s), the scientific conclusions
and grounds recommending the variation to the terms of the marketing authorisation and an
annex indicating the new safety warnings and key risk minimisation recommendations to be
included in the relevant sections of the product information, as applicable;
• in the case of a CMDh position to suspend the marketing authorisation(s), the scientific conclusions
together with the grounds for suspension and conditions for lifting the suspension;
• in the case of a CMDh position to revoke the marketing authorisation(s), the scientific conclusions
together with the grounds for revocation;
• divergent position(s) for the CMDh members, where applicable.
The final assessment conclusions and recommendations shall be published by the Agency in the
European medicines web-portal [DIR Art 107l] (VII.C.7.).
If the CMDh position is reached by consensus:
The position agreed including the action to be taken is recorded by the chairperson in the minutes of
the CMDh meeting where agreed.
The chairman shall send the agreed CMDh position [DIR Art 107g(2)] and its appendices to the
marketing authorisation holder(s) and competent authorities in Member States.
Further to receipt of the CMDh position stating that regulatory action to the concerned marketing
authorisation is necessary, the competent authorities in Member States shall adopt necessary
measures to vary, suspend or revoke the marketing authorisation(s) concerned in accordance with the
timetable for implementation determined in the agreed position [DIR Art 107g(2)].
In case the position of the CMDh agreed that variation to the terms of marketing authorisation is
required, the marketing authorisation holder(s) shall submit the relevant variation to that effect within
the timetable for implementation [DIR Art 107g(2)] as appended to the agreed position.
If the CMDh position is reached by majority vote:
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The majority position on the action to be taken is recorded by the chairman in the minutes of the
CMDh meeting where agreed.
The majority position of the CMDh together with its annexes and its appendices, including translations
in all EU official languages where applicable, shall be forwarded to the European Commission [DIR Art
107g(2)]. The position of the CMDh should also be forwarded to the competent authorities in Member
States.
Further to receipt of a CMDh position stating that regulatory action to the concerned marketing
authorisation is necessary, the European Commission shall adopt decision(s) [DIR Art 107g(2)]
addressed to the competent authorities in Member States in order for them to vary, suspend or revoke
the marketing authorisation(s) of nationally authorised product(s) which is addressed to marketing
authorisation holders.
Further to receipt of the decision from the European Commission, the competent authorities in Member
States shall take the necessary measures to maintain, vary, suspend or revoke the marketing
authorisation(s) within 30 days [DIR Art 107g(2)].
VII.C.4.3. Relationship between PSUR and risk management plan
The general relationship between the risk management plan (RMP) and the PSUR is described in
Module V, while an overview of the common RMP/PSUR modules is provided in VII.C.4.3.1..
During the preparation of a PSUR, the marketing authorisation holder should consider whether any
identified or potential risks discussed within the PSUR is important and requires an update of the RMP.
In these circumstances, updated revised RMP including the new important safety concern should be
submitted with the PSUR and assessed in parallel, following the timetable for the assessment of PSUR
as described above.
If important safety concerns are identified by the national competent authorities in the Member States
during the assessment of a PSUR and no updated RMP or no RMP has been submitted,
recommendations should be made to submit an update or a new RMP within a defined timeline.
VII.C.4.3.1. PSUR and risk management plan – common modules
The proposed modular formats for the PSUR and the RMP aim to address duplication and facilitate
flexibility by enabling common PSUR/RMP sections to be utilised interchangeably across both reports.
Common sections with the above mentioned reports are identified in Table VII.1.:
Table VII.1. Common sections between PSUR and RMP
PSUR section RMP section
Section 3 – “Actions taken in the reporting
interval for safety reasons”
Part II, module SV – “Post-authorisation
experience”, section “Regulatory and marketing
authorisation holder action for safety reason”
Sub-section 5.2 – “Cumulative and interval
patient exposure from marketing experience”
Part II, module SV – “Post-authorisation
experience”, section “Non-study post-
authorisation exposure”
Sub-section 16.1 – “Summary of safety concerns” Part II, module SVIII – “Summary of the safety
concerns” (as included in the version of the RMP
which was current at the beginning of the PSUR
reporting interval)
Sub-section 16.4 – “Characterisation of risks” Part II, Module SVII – “Identified and potential
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PSUR section RMP section
risks”
Sub-section 16.5 – “Effectiveness of risk
minimisation (if applicable)”
Part V – “Risk minimisation measures”, section
“Evaluation of the effectiveness of risk
minimisation activities”
VII.C.5. EU-specific requirements for periodic safety update reports
The scientific evaluation of the risk-benefit balance of the medicinal product included in the PSUR
detailed in VII.B.5. shall be based on all available data, including data from clinical trials in
unauthorised indications and populations according to the provisions of DIR Art 107b and IR Art 34(1).
The EU-specific requirements should be included in the PSUR EU regional appendix.
VII.C.5.1. PSUR EU regional appendix, sub-section “Proposed product
information”
The assessment of the need for amendments to the product information is incorporated within the
PSUR assessment procedure in the EU. The regulatory opinion/position should include
recommendations for updates to product information where needed. Marketing authorisation holders
should provide the necessary supportive documentation and references within the PSUR or in this
appendix to facilitate this.
Within the PSUR, the marketing authorisation holder is required to consider the impact of the data and
evaluations presented within the report, on the marketing authorisation. Based on the evaluation of
the cumulative safety data and the risk-benefit analysis, the marketing authorisation holder shall draw
conclusions in the PSUR as to the need for changes and/or actions, including implications for the
approved SmPC(s) for the product(s) for which the PSUR is submitted [IR Art 34 (5)].
In this sub-section, the marketing authorisation holder should provide the proposals for product
information (SmPC and package leaflet) based on the above mentioned evaluation. These should be
based on all EU authorised indications.
A track change version of the proposed SmPCs and package leaflets based on the assessment and
conclusions of the PSUR should be provided. For centrally authorised medicinal products, the proposed
product information should also be submitted to Module 1.3.1 of the Electronic Common Technical
Document (eCTD).
All the SmPCs and packages leaflets covered by the PSUR and in effect at the data lock point, should
be reviewed to ensure that they reflect the appropriate information according to the cumulative data
included and analysed in the PSUR.
Amendments to the product information should not be postponed or delayed until the PSUR submission
and amendments not related to the information presented in the PSUR, should not be proposed within
the PSUR procedure. It is the obligation of the marketing authorisation holder to submit a variation in
accordance with the Regulation (EC) No 1234/2008 on variations to the terms of a marketing
authorisation.
A brief description of ongoing procedures (e.g. variations) to update the product information should be
provided in this section.
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VII.C.5.2. PSUR EU regional appendix, sub-section “Proposed additional
pharmacovigilance and risk minimisation activities”
Considering the provision established in IR Art 34 (5), this sub-section should include proposals for
additional pharmacovigilance and additional risk minimisation activities based on the conclusions and
actions of the PSUR, including a statement of the intention to submit a RMP or an updated RMP when
applicable.
VII.C.5.3. PSUR EU regional appendix, sub-section “Summary of ongoing
safety concerns”
In order to support the information provided in the PSUR section 16.1 “Summary of safety concerns”
(see VII.B.5.16.1.), Table 1.10 (according to the current RMP template) “Summary – Ongoing safety
concerns” should be included in this PSUR sub-section. This table should be extracted from the version
of RMP available at the beginning of the PSUR reporting interval (see Module V).
VII.C.5.4. PSUR EU regional appendix, sub-section “Reporting of results
from post-authorisation safety studies”
Findings from both interventional and non-interventional (for further guidance see Module VIII) post-
authorisation safety studies (PASS) should be reported in the PSUR. While the marketing authorisation
holder should inform competent authorities in Member States and the Agency as applicable about any
new information that may impact on the risk-benefit balance immediately, the PSUR should provide
comprehensive information on the findings of all PASS, both interventional and non-interventional, in
PSUR sections 7 and 8 respectively.
Final study reports for studies conducted with the primary aim of identifying, characterising or
quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the
effectiveness of risk management measures which were completed during the reporting interval should
also be included as an annex to the PSUR. For such studies discontinued during the reporting interval,
the reasons for stopping the study should also be explained.
If an important safety concern has been identified in the course of a study, regardless of whether it
has been detected through pre-specified methods and whether the study is considered a PASS, the
marketing authorisation holder and specifically the qualified person responsible for pharmacovigilance
(QPPV) will have informed the relevant competent authorities in Member States immediately.
PSURs should not be used as the initial communication method either for the submission of final study
reports to the competent authorities in Member States or for the notification of any new information
that might influence the evaluation of the risk-benefit balance.
VII.C.5.5. PSUR EU regional appendix, sub-section “Effectiveness of risk
minimisation”
Risk minimisation activities are public health interventions intended to prevent the occurrence of an
adverse drug reaction(s) associated with the exposure to a medicinal product or to reduce its severity
should it occur. The success of risk minimisation activities in delivering these objectives needs to be
evaluated throughout the lifecycle of a product to ensure that the burden of adverse reactions is
minimised and hence the overall risk-benefit balance is optimised. In accordance with section
VII.B.5.16.5., evaluation of broad global experience should be reflected in the body of the report, when
provides insights into the effectiveness of risk minimisation activities in any country or region that may
have utility in other countries or regions are of particular interest .
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This sub-section should additionally provide an evaluation of the effectiveness of routine and/or
additional risk minimisation activities specifically relevant to an EU context. This should take account of
regulatory imposed obligations for implementation of risk minimisation measures in addition to the
overall requirement for monitoring of safety and benefit-risk. Results of any studies to assess the
impact or other formal assessment(s) of risk minimisation activities in the EU should be included when
available. As part of this critical evaluation, the marketing authorisation holder should make
observations on factors contributing to the success or weakness of risk minimisation activities. If a
particular risk minimisation strategy proves ineffective, then alternative activities need to be put in
place. In certain cases, it may be judged that risk minimisation cannot control the risks to the extent
possible to ensure a positive risk-benefit balance and that the medicinal product needs to be withdrawn
either from the market or restricted to those patients in whom the benefits outweigh the risks. More
extensive guidance on monitoring the effectiveness of risk minimisation activities is included in Module
XVI. As a principle, the marketing authorisation holder should distinguish in their evaluation between
implementation success and attainment of the intended outcome.
VII.C.6. Quality systems and record management systems for PSURs in the
EU network
VII.C.6.1. Quality systems and record management systems at the level of
the marketing authorisation holder
Specific quality system procedures and processes shall be in place in order to ensure the update of
product information by the marketing authorisation holder in the light of scientific knowledge, including
the assessments and recommendations made public via the European medicines web-portal, and on
the basis of a continuous monitoring by the marketing authorisation holder of information published on
the European medicines web-portal [IR Art 11(1)(f)].
It is the responsibility of the marketing authorisation holder to check regularly the list of EU reference
dates and frequency of submission published in the European medicines web-portal to ensure
compliance with the PSUR reporting requirements for their medicinal products (see VII.C.3.).
Systems should be in place to schedule the production of PSURs according to:
• the list of EU reference dates and frequency of PSURs submission; or
• the conditions laid down in the marketing authorisation; or
• the standard PSUR submission schedule established according to DIR Art 107c(2) for products
authorised before 2 July 2012 (for centrally authorised products) and 21 July 2012 (for nationally
authorised products) as applicable (without any conditions in their marketing authorisation or not
included in the list of EU references dates and frequency of submission or not affected by the
derogation established in [DIR Art 107b(3)]); or
• ad hoc requests for PSURs by a competent authority in a Member State or the Agency.
For those medicinal products where the submission of an RMP is not required, the marketing
authorisation holder should maintain on file a specification of important identified risks, important
potential risks and missing information in order to support the preparation of the PSURs.
The marketing authorisation holder should have procedures in place to follow the requirements
established by the Agency for the submission of PSURs.
The QPPV shall be responsible for the establishment and maintenance of the pharmacovigilance system
[DIR Art 104(e)] and therefore should ensure that the pharmacovigilance system in place enables the
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1)
EMA/816292/2011 Rev 1 Page 59/68
compliance with the requirements established for the production and submission of PSURs. In relation
to the medicinal products covered by the pharmacovigilance system, specific additional responsibilities
of the QPPV in relation to PSURs should include:
• ensuring the necessary quality, including the correctness and completeness, of the data submitted
in the PSURs;
• ensuring full response according to the timelines and within the procedure agreed (e.g. next PSUR)
to any request from the competent authorities in Member States and the Agency related to PSURs;
• awareness of the PSUR and assessment report conclusions, PRAC recommendations, CHMP
opinions, CMDh positions and European Commission decisions in order to ensure that appropriate
action takes place.
The record retention times for product-related documents in Module I also apply to PSURs and source
documents related to the creation of PSURs, including documents related to actions taken for safety
reasons, clinical trials and post-authorisation studies, relevant benefit information and documents
utilised for the calculation of patient exposure.
VII.C.6.2. Quality systems and record management systems at the level of
the European Medicines Agency
The application of the Agency’s quality system (see Module I) should support compliance by the
Agency when fulfilling its tasks and responsibilities for the management of PSUR procedures and EU
single assessments.
The Agency should have in place a process to technically validate the completeness of PSUR
submissions.
Line listings and summary tabulations from the EudraVigilance database utilised to support the PSUR
assessment should be created using reports by means of the EudraVigilance data analysis system.
Effective communication and circulation of PSURs and related documents is crucial for the successful
completeness of the procedure; therefore processes have to be in place for the circulation of
documents between the Agency, marketing authorisation holders, the Commission and the competent
authorities in Member States. Where applicable, the procedures should establish the necessity for
quality checks with the aim to remove any information of a personal or commercially confidential
nature.
Written procedures should reflect the different steps to follow for the maintenance of the list of EU
references dates and frequency of submission of PSURs published by the Agency in the European
medicines web-portal (see VII.C.3.).
Prior to the publication of summaries of PSUR assessment reports in the European medicines web-
portal (see VII.C.7.) the appropriate personnel at the Agency should adhere to the procedures
established for web publication of documents produced by the Agency or competent authorities in the
Member States.
All records related to PSURs created by the Agency’s staff members, experts or consultants are the
property of the Agency and all PSURs and related documents received are in the custody of the
Agency. Both types of PSURs records (created or received by the Agency) are subject to the Agency’s
overall control via the PSUR repository set up according to the provisions laid down in REG Art 25a.
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The Agency’s policy on records management (EMEA/590678/2007)23, provides the basis for a
consistent, sustainable and efficient records management program and it has been developed in
accordance with the commonly recognised international standard for records management, “ISO
15489-1:2001 Information and documentation – Records management24”. According to the records
classification stated by the Agency’s policy, PSURs would be considered business, legal, evidential and
research/historical value records.
The record retention times for product-related documents in Module I also apply to PSUR- system
related documents (e.g. standard operating procedures) and PSUR -related documents (e.g. PSURs,
assessment reports, the data retrieved from the EudraVigilance database or other data used to support
the PSUR assessment).
VII.C.6.3. Quality systems and record management systems at the level of
the competent authorities in Member States
Each competent authority in the Member States shall have in place a pharmacovigilance system [DIR
Art 101] for the surveillance of medicinal products and for receipt and evaluation of all
pharmacovigilance data including PSURs. For the purpose of operating its tasks relating to PSURs in
addition to the pharmacovigilance system the national competent authorities in Member States should
implement a quality system (see Module I).
Competent authorities in the Member States should monitor marketing authorisation holders for
compliance with regulatory obligations for PSURs. Additionally, competent authorities should exchange
information in cases of non-compliance and take appropriate regulatory actions as required.
No PSUR assessment at EU level is foreseen for purely nationally authorised products authorised in
only one Member State; therefore the national competent authority in the Member State where the
medicinal product is authorised should have procedures in place for the assessment of PSURs related
to those medicinal products.
The procedures established by the national competent authorities in Member States for the
performance of the EU single assessment of PSURs, should be in line with the procedures established
by the Agency for the coordination of PSUR assessment in the EU regulatory network (see VII.C.4.).
These procedures should establish effective communication across the EU regulatory network and the
actions to be taken regarding the variation, suspension or revocation of the marketing authorisation
following the PRAC recommendations, CHMP opinion, CMDh position and European Commission
decision as applicable.
The procedures established by the Agency for the use of the PSUR repository to support the single
assessment, should be followed by the national competent authorities in Member States.
Where tasks related to PSUR procedures are delegated to third parties, the national competent
authorities in Member States should ensure that they are subject to a quality system in compliance
with the obligations provided by the European legislation.
The record retention times for product-related documents in Module I also apply to PSUR- system
related documents (e.g. standard operating procedures) and PSUR -related documents (e.g. PSURs,
assessment reports, the data retrieved from the EudraVigilance database or other data used to support
the PSUR assessment).
23 www.ema.europa.eu
24 www.ISO.org
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http://www.ema.europa.eu/
http://www.iso.org/
VII.C.7. Transparency
VII.C.7.1. Publication of PSUR-related documents on the European
medicines and national medicines web-portals
The following documents shall be made publicly available by means of the European medicines web-
portal [DIR Art 107l, REG Art 26(g)]:
• list of EU reference dates and frequency of submission of PSURs (see VII C.3.);
• final assessment conclusions of the adopted assessment reports;
• PRAC recommendations including relevant annexes;
• CMDh position including relevant annexes and where applicable, detailed explanation on scientific
grounds for any differences with the PRAC recommendations;
• CHMP opinion including relevant annexes and where applicable, detailed explanation on scientific
grounds for any differences with the PRAC recommendations;
• European Commission decision.
The version and date of publication are reflected in each document as they define the issue of the
PRAC recommendations, CHMP opinions, CMDh positions and European Commission decisions at a
certain point of time.
Links between the European medicines web-portal and the National medicines web-portals should be
made whenever possible and relevant.
Any personal or confidential data made public by the Agency or the competent authorities in Member
States as referred to in paragraphs 2 and 3 of Article 106a of Directive 2001/83/EC shall be deleted
unless considered necessary in terms of protection of the public health [DIR Art 106a(4)].
VII.C.8. Renewal of marketing authorisations
Marketing authorisations need to be renewed after 5 years on the basis of a re-evaluation of the risk-
benefit balance in order to continue to be valid to place the product on the market. This renewal is
irrespective of whether the marketing authorisation is suspended. Further details on the procedure and
the documentation requirements can be found in the current versions of the “Guideline on Processing
of Renewals in the Centralised Procedure” (EMEA/CHMP/2990/00) for Centralised products and the
“CMDh Best Practice Guide on the processing of renewals in the MRP/DCP” (CMDh/004/2005) for other
products.
No PSURs, addendum reports and summary bridging reports should be submitted within the renewal
application. The clinical overview should include an addendum containing the relevant sections for the
re-assessment of the risk-benefit balance of the medicinal product. These sections are identified in the
above-mentioned guidelines for renewal. Marketing authorisation holders are advised to consider this
GVP Module VII as guidance for the preparation of the addendum to the clinical overview.
Following the submission of a renewal application, the PRAC may be consulted for medicinal products
authorised through the centralised procedure as regards safety issues. For nationally authorised
products, including those authorised through the mutual recognition or decentralised procedure, the
PRAC may also be consulted upon request by a competent authority in a Member State on the basis of
safety concerns.
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Conditional marketing authorisations should be renewed annually [REG Art 14(7)]. Further details on
the procedure and the documentation to be submitted can be found in the “Guideline on the scientific
application and the practical arrangements necessary to implement Commission Regulation (EC) No
507/2006 on the conditional marketing authorisation for medicinal products for human use falling
within the scope of regulation (EC) no 726/2004” (EMEA/509951/2006).
VII.C.9. Transition and interim arrangements
VII.C.9.1. Submission and availability of documents before the Agency’s
repository is in place
The Agency shall, in collaboration with the competent authorities in Member States and the European
Commission set up and maintain a repository for PSURs and the corresponding assessment reports so
that they are fully and permanently accessible to European Commission, the competent authorities in
Member States, the PRAC, the CHMP and the CMDh [REG Art 25a].
The repository shall undergo an independent audit before the functionalities are announced by the
Agency’s management board [REG Art 25a].
As established in the transitional provisions introduced in Directive 2010/84/EU Art 2(7), until the
Agency can ensure the functionalities agreed for the repository, marketing authorisation holders under
the obligation to submit PSURs irrespective of whether the medicinal product is authorised in one or
more Member States and irrespective of whether the active substance or combination of active
substances is on the EU reference date list shall submit the PSURs to all competent authorities in
Member States in which the medicinal products are authorised. For the substances or combination of
active substances subject to the EU single assessment, and for which an EU reference date has been
established, the PSURs should be also sent to the Agency.
The competent authorities in Member States requirements for the submission of PSURs during this
transitional period are published in the Agency web-site25.
From 12 months after the functionalities of the repository have been established and have been
announced by the Agency, the marketing authorisation holders shall submit the PSURs electronically to
the Agency regardless of the authorisation procedure of the medicinal product [DIR Art 107b(1)]. The
competent authorities in Member States shall ensure that this obligation applies as required [DIR Art
2(7)].
Once the structured electronic format “ePSUR”, based on content agreed in the ICH-E2C(R2), becomes
available, marketing authorisation holders will have the possibility to submit PSURs and related
documents automatically via an electronic gateway.
Until the repository is in place, the relevant documents should be circulated as follows:
• The preliminary assessment report created by the PRAC Rapporteur/Member State within 60 days
of the start of the procedure should be circulated to the Agency and the members of the PRAC
through a dedicated mailbox. The Agency should send the report to the concerned marketing
authorisation holder(s);
• members of the PRAC should circulate their comments through a dedicated mailbox by Day 90 on
the PRAC Rapporteur/Member State preliminary assessment report;
25 www.ema.europa.eu
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http://www.ema.europa.eu/
• comments by the marketing authorisation holders(s) by Day 90 on the PRAC Rapporteur/Member
State preliminary assessment report, should be submitted to the Agency, PRAC Rapporteur and all
members of the PRAC, according to the instructions for submission published by the Agency;
• updated PRAC Rapporteur/Member State assessment report created within 15 days (i.e. by Day
105) should be circulated to the Agency and members of the PRAC through a dedicated mailbox.
The Agency should forward the updated PRAC Rapporteur/Member State assessment report to the
marketing authorisation holders concerned.
Further to adoption, the Agency should send the CHMP opinion together with its annexes and
appendices to the European Commission, marketing authorisation holder(s) and competent authorities
in Member States, through secure email until the repository is in place.
VII.C.9.2. Quality systems and record management systems at the level of
the competent authorities in Member States
Special considerations should be taken for the management of the PSURs submitted to the concerned
competent authorities in Member States until the Agency can ensure the functionalities agreed for the
PSUR repository and 12 months after the establishment of the repository according to the transitional
provisions.
VII.C.9.3. Publication of the EU list of union references dates and start of
the EU- PSUR single assessment procedure
As stated in VII.C.3.6., the list of EU reference dates and frequency of submission should be published
in the European medicines web-portal, nevertheless, the EU single assessment procedure for
substances included only in nationally authorised products, detailed in VII.C.4.2.2., and VII.C.4.2.4.
will be delayed until funds are available.
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VII.APPENDICES
VII.Appendix 1. Examples of tabulations for estimated exposure and
adverse events/reactions data
Marketing authorisation holders can modify these examples tabulations to suit specific situations, as
appropriate.
Table VII.2. Estimated cumulative subject exposure from clinical trials
Estimates of cumulative subject exposure, based upon actual exposure data from completed clinical
trials and the enrolment/randomisation schemes for ongoing trials.
Treatment Number of Subjects
Medicinal product
Comparator
Placebo
Table VII.3. Cumulative subject exposure to investigational drug from completed clinical trials by age
and sex
Number of subjects
Age range Male Female Total
Data from completed trials as of [date]
Table VII.4. Cumulative subject exposure to investigational drug from completed clinical trials by
racial/ethnic group
Racial/ethnic group Number of subjects
Asian
Black
Caucasian
Other
Unknown
Total
Data from completed trials as of [date]
Table VII.5. Cumulative exposure from marketing experience
Indication Sex Age (years) Dose Formulation Region
M
ale
Fem
ale
2 to ≤
16
>
16 to 65
>
65
U
nknow
n
<
40
≥
40
U
nknow
n
Intravenous
O
ral
EU
Japan
C
olom
bia
U
S
/C
anada
O
ther
Overall
Depression
Migraine
Table VII.5 includes cumulative data obtained from day/month/year throughout day/month/year, where available
Guideline on good pharmacovigilance practices (GVP) – Module VII (Rev 1)
EMA/816292/2011 Rev 1 Page 65/68
Table VII.6. Interval exposure from marketing experience
Indication Sex Age (years) Dose Formulation Region
M
ale
Fem
ale
2 to ≤
16
>
16 to 65
>
65
U
nknow
n
<
40
≥
40
U
nknow
n
Intravenous
O
ral
EU
Japan
C
olom
bia
U
S
/C
anada
O
ther
Depression
Migraine
Table VII. 6 includes interval data obtained from day/month/year throughout day/month/year
Table VII.7. Cumulative tabulation of serious adverse events from clinical trials
System Organ Class
Preferred Term
Investigational
medicinal
product
Blinded
Active
comparator
Placebo
Blood and lymphatic system
disorders
Anaemia
Bone marrow necrosis
Cardiac disorders
Tachycardia
Ischaemic cardiomyopathy
Table VII.8. Numbers of adverse reactions by preferred term from post-authorisation sources*
SOC
MedDRA
PT
Spontaneous, including competent authorities (worldwide)
and literature
Non-interventional post-
marketing study and
reports from other solicited
sources **
Serious Non-serious
Total
Spontaneous
Serious
Interval Cumulative Interval Cumulative Cumulative Interval Cumulative
<SOC 1>
<PT>
<PT>
<PT>
<SOC 2>
<PT>
<PT>
<PT>
<PT>
* Non-interventional post-authorisation studies, reports from other solicited sources and spontaneous ICSRs (i.e.,
reports from healthcare professionals, consumers, competent authorities (worldwide), and scientific literature)
** This does not include interventional clinical trials.
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VII.Appendix 2. Example of tabular summary of safety signals that were
ongoing or closed during the reporting interval
Table VII.9. The tabular summary below is a fictitious example of tabular summary of safety signals
ongoing or closed during the reporting interval
Reporting interval: DD-MMM-YYYY to DD-MMM-YYYY
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Page 67/68
Explanatory notes:
Signal term:
• A brief descriptive name of a medical concept for the signal. This may evolve and be refined as the
signal is evaluated. The concept and scope may or may not be limited to specific MedDRA term(s),
depending on the source of signal.
Date detected:
• Month and year the marketing authorisation holder became aware of the signal.
Status:
• Ongoing: Signal under evaluation at the data lock point of the PSUR. Anticipated completion date,
if known, should be provided.
• Closed: Signal for which evaluation was completed before the data lock point of the PSUR.
Note: A new signal of which the marketing authorisation holder became aware during the reporting
interval may be classified as closed or ongoing, depending on the status of the signal evaluation at the
end of the reporting interval of the PSUR.
Date closed:
• Month and year when the signal evaluation was completed.
Source of signal:
• Data or information source from which a signal arose. Examples include, but may not be limited to,
spontaneous reports, clinical trial data, scientific literature, and non-clinical study results, or
information request or inquiries from a competent authority (worldwide).
Reason for evaluation and summary of key data:
• A brief summary of key data and rationale for further evaluation.
Action(s) taken or planned:
State whether or not a specific action has been taken or is planned for all closed signals that have been
classified as potential or identified risks. If any further actions are planned for newly or previously
identified signals under evaluation at the data lock point, these should be listed, otherwise leave blank
for ongoing signals.
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Page 68/68
VII.A. Introduction
VII.B. Structures and processes
VII.B.1. Objectives of the periodic update safety report (PSUR)
VII.B.2. Principles for the evaluation of the risk-benefit balance within PSURs and scope of the information to be included
VII.B.3. Principles for the preparation of PSURs
VII.B.4. Reference information
VII.B.5. Format and contents of the PSUR
PSUR title page
PSUR executive summary
PSUR table of contents
VII.B.5.1. PSUR section “Introduction”
VII.B.5.2. PSUR section “Worldwide marketing authorisation status"
VII.B.5.3. PSUR section “Actions taken in the reporting interval for safety reasons”
VII.B.5.4. PSUR section “Changes to reference safety information”
VII.B.5.5. PSUR section “Estimated exposure and use patterns”
VII.B.5.5.1. PSUR sub-section “Cumulative subject exposure in clinical trials”
VII.B.5.5.2. PSUR sub-section “Cumulative and interval patient exposure from marketing experience”
VII.B.5.6. PSUR section “Data in summary tabulations”
VII.B.5.6.1. PSUR sub-section “Reference information”
VII.B.5.6.2. PSUR sub-section “Cumulative summary tabulations of serious adverse events from clinical trials”
VII.B.5.6.3. PSUR sub-section “Cumulative and interval summary tabulations from post-marketing data sources”
VII.B.5.7. PSUR section “Summaries of significant findings from clinical trials during the reporting interval”
VII.B.5.7.1. PSUR sub-section “Completed clinical trials”
VII.B.5.7.2. PSUR sub-section “Ongoing clinical trials”
VII.B.5.7.3. PSUR sub-section “Long term follow-up”
VII.B.5.7.4. PSUR sub-section “Other therapeutic use of medicinal product”
VII.B.5.7.5. PSUR sub-section “New safety data related to fixed combination therapies”
VII.B.5.8. PSUR section “Findings from non-interventional studies”
VII.B.5.9. PSUR section “Information from other clinical trials and sources”
VII.B.5.9 1. PSUR sub-section “Other clinical trials”
VII.B.5.9 2. PSUR sub-section “Medication errors”
VII.B.5.10. PSUR section “Non-clinical data”
VII.B.5.11. PSUR section “Literature”
VII.B.5.12. PSUR section “Other periodic reports”
VII.B.5.13. PSUR section “Lack of efficacy in controlled clinical trials”
VII.B.5.14. PSUR section “Late-breaking information”
VII.B.5.15. PSUR section “Overview of signals: new, ongoing, or closed”
VII.B.5.16. PSUR section “Signal and risk evaluation”
VII.B.5.16.1. PSUR sub-section “Summary of safety concerns”
VII.B.5.16.2. PSUR sub-section “Signal evaluation”
VII.B.5.16.3. PSUR sub-section “Evaluation of risks and new information”
VII.B.5.16.4. PSUR sub-section “Characterisation of risks”
VII.B.5.16.5. PSUR sub-section: “Effectiveness of risk minimisation (if applicable)”
VII.B.5.17. PSUR section “Benefit evaluation”
VII.B.5.17.1. PSUR sub-section “Important baseline efficacy and effectiveness information”
VII.B.5.17.2. PSUR sub-section “Newly identified information on efficacy and effectiveness”
VII.B.5.17.3. PSUR sub-section “Characterisation of benefits”
VII.B.5.18. PSUR section “Integrated benefit-risk analysis for authorised indications”
VII.B.5.18.1. PSUR sub-section “Benefit-risk context - medical need and important alternatives”
VII.B.5.18.2. PSUR sub-section “Benefit-risk analysis evaluation”
VII.B.5.19. PSUR section “Conclusions and actions”
VII.B.5.20. Appendices to the PSUR
VII.B.5.21. Mapping signals and risks to PSUR sections/sub-sections
VII.B.6. Quality systems for PSURs at the level of marketing authorisation holders
VII.B.7. Training of staff members related to the PSUR process
VII.C. Operation of the EU network
VII.C.1. PSUR process in the EU - General process
VII.C.2. Standard submission schedule of PSURs
VII.C.3. List of European Union reference dates and frequency of submission of PSURs19F
VII.C.3.1. Objectives of the EU reference dates list
VII.C.3.2. Description of the EU reference dates list
VII.C.3.3. Application of the list of EU reference dates to submission of PSURs
VII.C.3.3.1. Submission of PSURs for medicinal products: general requirement
VII.C.3.3.2. Submission of PSURs for generic, well-established use, traditional herbal and homeopathic medicinal products
VII.C.3.3.3. Submission of PSURs for fixed dose combination products
VII.C.3.3.4. Submission of PSURs on demand of a competent authority in a Member State
VII.C.3.4. Criteria used for defining the frequency of submission of PSURs
VII.C.3.5. Maintenance of the list of EU reference dates
VII.C.3.5.1. General principles
VII.C.3.5.2. Requests from marketing authorisation holders to amend the list of EU reference dates
VII.C.3.6. Publication of the list
VII.C.3.7. Amendment of the marketing authorisation according to the list of EU reference dates
VII.C.4. Processes for PSUR Assessment in the EU network
VII.C.4.1. PSURs for purely nationally authorised medicinal products
VII.C.4.2. Medicinal products authorised in more than one Member State
VII.C.4.2.1. Assessment of PSURs for a single centrally authorised medicinal product
VII.C.4.2.2. Assessment of PSURs for medicinal products subject to different marketing authorisations containing the same active substance (EU single assessment)
VII.C.4.2.3. Single assessment including at least one centrally authorised product leading to a CHMP opinion
VII.C.4.2.4. Single assessment not including centrally authorised product leading to a CMDh position
VII.C.4.3. Relationship between PSUR and risk management plan
VII.C.4.3.1. PSUR and risk management plan – common modules
VII.C.5. EU-specific requirements for periodic safety update reports
VII.C.5.1. PSUR EU regional appendix, sub-section “Proposed product information”
VII.C.5.2. PSUR EU regional appendix, sub-section “Proposed additional pharmacovigilance and risk minimisation activities”
VII.C.5.3. PSUR EU regional appendix, sub-section “Summary of ongoing safety concerns”
VII.C.5.4. PSUR EU regional appendix, sub-section “Reporting of results from post-authorisation safety studies”
VII.C.5.5. PSUR EU regional appendix, sub-section “Effectiveness of risk minimisation”
VII.C.6. Quality systems and record management systems for PSURs in the EU network
VII.C.6.1. Quality systems and record management systems at the level of the marketing authorisation holder
VII.C.6.2. Quality systems and record management systems at the level of the European Medicines Agency
VII.C.6.3. Quality systems and record management systems at the level of the competent authorities in Member States
VII.C.7. Transparency
VII.C.7.1. Publication of PSUR-related documents on the European medicines and national medicines web-portals
VII.C.8. Renewal of marketing authorisations
VII.C.9. Transition and interim arrangements
VII.C.9.1. Submission and availability of documents before the Agency’s repository is in place
VII.C.9.2. Quality systems and record management systems at the level of the competent authorities in Member States
VII.C.9.3. Publication of the EU list of union references dates and start of the EU- PSUR single assessment procedure
VII.APPENDICES
VII.Appendix 1. Examples of tabulations for estimated exposure and adverse events/reactions data
VII.Appendix 2. Example of tabular summary of safety signals that were ongoing or closed during the reporting interval
29.07.2014
Datei
PD
See websites for contact details
European Medicines Agency www.ema.europa.eu
Heads of Medicines Agencies www.hma.eu
The European Medicines Agency is
an agency of the European Union
© European Medicines Agency and Heads of Medicines Agencies, 2013.
Reproduction is authorised provided the source is acknowledged.
19 April 2013
EMA/170043/2013
Guideline on good pharmacovigilance practices (GVP)
Annex II – Templates: Cover page of Periodic Safety Update Report (PSUR)
(Rev 1)
Draft of first version finalised by the Agency in collaboration with
Member States and submitted to ERMS FG (as part of GVP M VII)
19 January 2012
Draft agreed by ERMS FG 24 January 2012
Draft adopted by Executive Director 20 February 2012
Released for public consultation 21 February 2012
End of consultation (deadline for comments) 18 April 2012
Revised draft of first version finalised by the Agency in collaboration with
Member States
20 June 2012
Revised draft agreed by ERMS FG 21 June 2012
Revised draft adopted by Executive Director as final (as part of GVP M
VII)
22 June 2012
Date for coming into effect 2 July 2012
Draft Revision 1* finalised by the Agency in collaboration with Member
States
21 March 2013
Draft Revision 1 agreed by ERMS FG 27 March 2013
Draft Revision 1 adopted by Executive Director as final 19 April 2013
Date for coming into effect of Revision 1 25 April 2013
*Note: Revision 1 contains the following:
- correcting “(Underline (Harmonised) EU Birth Date)” to “(Underline the International Birth Date)”.
Guideline on good pharmacovigilance practices (GVP) – Annex II – PSUR Cover page
(Rev 1)
EMA/170043/2013 Page 2/2
PERIODIC SAFETY UPDATE REPORT
for
ACTIVE SUBSTANCE(S): <INN>
ATC CODE(S): <Code(s)>
MEDICINAL PRODUCTS COVERED:
Invented name of the
medicinal product(s)
Marketing
authorisation
number(s)
Date(s) of
authorisation
(Underline the
International Birth
Date)
Marketing
authorisation
holder
<> <> <> <>
<> <> <> <>
AUTHORISATION PROCEDURE in the EU:
<Centralised/Mutual Recognition/Decentralised/Purely National>
INTERNATIONAL BIRTH DATE (IBD): <Date>
EUROPEAN UNION REFERENCE DATE (EURD): <Date>
INTERVAL COVERED BY THIS REPORT:
From <date> to <date (i.e. data lock point)>
DATE OF THIS REPORT:
<Date>
OTHER INFORMATION:
<Other identifying or clarifying information if necessary>
MARKETING AUTHORISATION HOLDER'S NAME AND ADDRESS:
<Name>
<Address>
<E-mail address> (contact person for the PSUR procedure)
NAME AND CONTACT DETAILS OF THE QPPV:
<Name>
<Address>
<Telephone number>
<Fax number>
<E-mail address>
SIGNATURE (QPPV or designated person): <Signature>
DISTRIBUTION LIST1
<Competent authority in the EU> <Number of copies>
1 For medicinal products authorised through the mutual recognition or decentralised procedure the Reference Member State
and the Concerned Member States should be indicated.
29.07.2014
Datei
PD
See websites for contact details
European Medicines Agency www.ema.europa.eu
Heads of Medicines Agencies www.hma.eu
The European Medicines Agency is
an agency of the European Union
© European Medicines Agency and Heads of Medicines Agencies, 2013.
Reproduction is authorised provided the source is acknowledged.
19 April 2013
EMA/395730/2012 Rev 1*
Guideline on good pharmacovigilance practices (GVP)
Module VIII Addendum I – Member States' requirements for transmission of
information on non-interventional post-authorisation safety studies (Rev 1)
Date for coming into effect of first version 2 July 2012
Date for coming into effect of Revision 1* 25 April 2013
*Note: Revision 1 contains the following:
- Specification in explanatory note no 4 that the notification to all Member States is made by the
Agency;
- Renaming of the document as Module VIII Addendum I (instead of Annex to Module VIII) in order to
avoid confusion with GVP Annexes which are applicable to all GVP Modules.
Guideline on good pharmacovigilance practices (GVP) – Module VIII Addendum I (Rev
I)
EMA/395730/2012 Rev 1 Page 2/2
The tables below specify Member States’ (MS) requirements for the transmission of information on
post-authorisation safety studies initiated, managed or financed by marketing authorisation holders
(MAHs) voluntarily or pursuant to an obligation.
These requirements are based on Directive 2001/83/EC Art 107 m-q and the GVP Module VIII. They do
not cover the situation of studies conducted in only one Member State that requests the study
according to Article 22a, in which case the MAH shall submit the draft protocol and the other study
information to the national competent authority of the Member State in which the study is conducted.
These tables cover the requirements for transmission of information to national regulatory authorities,
not to ethics committees, national review boards or other bodies in place according to national
legislation.
Table VIII Add I.1. Studies imposed as an obligation by a competent authority
Study protocols, updated study
protocols following substantial
amendments, final study reports 1
Progress
reports if
requested 1
Direct
transmission by
MAH to MS 2
Transmission by
MAH to MS via
PRAC 3
Direct
transmission by
MAH to MS 2
Member States where the study is
conducted
All All
Member States acting as Rapporteur or
RMS for the medicinal product **
All All
Member States where the medicinal
product is authorised, but not acting as
Rapporteur of RMS for the medicinal
product **
All DE
1 Study information should also be entered and maintained in the EU PAS Register.
2 Final study protocols, substantial amendments to study protocol, any progress reports, abstracts of final study
report and final study reports to be transmitted by marketing authorisation holders to Member States according to
national procedures.
3 Information to be transmitted by marketing authorisation holders to the Agency and all PRAC members in the
context of the oversight of post-authorisation safety studies by the PRAC as described in Directive 2001/83/EC Art
107 n-p.
** even if study not conducted in the Member State
Table VIII Add I.2. Studies initiated, managed or financed voluntarily by MAHs
Study protocols, updated study protocols
following substantial amendments, progress
reports if requested and final study reports
Transmission by MAH via
notification from EU PAS
Register 4
Additional
transmission by MAH
to MS 5
Member States where the study is conducted
All
AT, BG, CZ, DE, ES,
IT, NL, PT, RO
Member States acting as Rapporteur or RMS
for the medicinal product **
All DE, DK, NL, PT, RO
Member States where the medicinal product is
authorised but not acting as Rapporteur or
RMS for the medicinal product **
All DE, RO
4 Notification message sent by the European Medicines Agency to all EU Member States with a link to the study
record
5 Information to be transmitted by marketing authorisation holders to Member States according to national
procedures.
** even if study not conducted in the Member State
29.07.2014
Datei
PD
See websites for contact details
European Medicines Agency www.ema.europa.eu
Heads of Medicines Agencies www.hma.eu
The European Medicines Agency is
an agency of the European Union
© European Medicines Agency and Heads of Medicines Agencies, 2013.
Reproduction is authorised provided the source is acknowledged.
19 April 2013
EMA/813938/2011 Rev 1*
Guideline on good pharmacovigilance practices (GVP)
Module VIII – Post-authorisation safety studies (Rev 1)
Draft of first version finalised by the Agency in collaboration with
Member States
19 January 2012
Draft agreed by ERMS FG 24 January 2012
Draft adopted by Executive Director 20 February 2012
Released for public consultation 21 February 2012
End of consultation (deadline for comments) 18 April 2012
Revised draft of first version finalised by the Agency in collaboration with
Member States
20 June 2012
Revised draft agreed by ERMS FG 21 June 2012
Revised draft adopted by Executive Director as final 22 June 2012
Date for coming into effect 2 July 2012
Draft Revision 1* finalised by the Agency in collaboration with Member
States
21 March 2013
Draft Revision 1 agreed by ERMS FG 27 March 2013
Draft Revision 1 adopted by Executive Director as final 19 April 2013
Date for coming into effect of Revision 1 25 April 2013
*Note: Revision 1 contains the following:
- Clarifications of the text following questions received from stakeholders regarding
scope of the guidance to EU and non-EU studies: page 5, section VIII.B.1.;
classification of a post-authorisation study as a PASS according to its main aim: page 6,
section VIII.B.3.;
study registration (study registration not limited to studies conducted in the EU and updates of
study record to be made preferably within two weeks): page 7, section VIII.B.4. and page 8,
section VIII.B.4.;
Guideline on good pharmacovigilance practices (GVP) – Module VIII (Rev 1)
EMA/813938/2011 Rev 1 Page 2/27
- Increased consistency with GVP Module V regarding the four categories of studies included in the risk
management plan: page 4, section VIII.A. and page 5, section VIII.B.1.;
- Amendments to make reference to published detailed guidance for the format and content of non-
interventional PASS protocols and final study reports: page 8, section VIII.B.5.1., page 10, section
VIII.B.5.1., page 12, section VIII.B.6.3.2., and page 15, section VIII.B.6.3.2.;
- Amendment of regulatory wording to use that adopted by the Agency or following legal advice
regarding that
in the procedure for imposing a PASS, the PRAC may adopt an advice with an assessment
report: page 17, sections VIII.C.2.a., VIII.C.2.b. and VIII.C.2.c.;
roles and responsibilities to marketing authorisation holders for non-interventional PASS apply
to studies imposed as an obligation as a condition to the marketing authorisation: page 19,
section VIII.C.4.1.;
- Editorial corrections and improvements: page 4, section VIII.A., page 5, section VIII.B.1., page 10,
section 9.6., and page 19, section VIII.C.4.1..
- Update of the cross-reference to the document “Member States’ requirements for transmission of
PASS information “ (now GVP Module VIII Addendum I).
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EMA/813938/2011 Rev 1 Page 3/27
Table of contents
VIII.A. Introduction .................................................................................... 4
VIII.B. Structures and processes ................................................................ 5
VIII.B.1. Scope ........................................................................................................... 5
VIII.B.2. Terminology .................................................................................................. 5
VIII.B.3. Principles ...................................................................................................... 6
VIII.B.4. Study registration .......................................................................................... 7
VIII.B.5. Study protocol ............................................................................................... 8
VIII.B.5.1. Format and content of the study protocol ....................................................... 8
VIII.B.5.2. Substantial amendments to the study protocol ............................................. 11
VIII.B.6. Reporting of pharmacovigilance data to competent authorities .......................... 11
VIII.B.6.1. Data relevant to the risk-benefit balance of the product ................................. 11
VIII.B.6.2. Reporting of adverse reactions/adverse events ............................................. 11
VIII.B.6.3. Study reports ........................................................................................... 12
VIII.B.6.3.1 Progress reports ...................................................................................... 12
VIII.B.6.3.2. Final study report ................................................................................... 12
VIII.B.7. Publication of study results ........................................................................... 15
VIII.B.7.1. Regulatory submission of manuscripts accepted for publication ....................... 16
VIII.B.8. Data protection ........................................................................................... 16
VIII.B.9. Quality systems, audits and inspections .......................................................... 16
VIII.B.10. Impact on the risk management system ....................................................... 16
VIII.C. Operation of the EU network .......................................................... 17
VIII.C.1. Scope ......................................................................................................... 17
VIII.C.2. Procedure for imposing post-authorisation safety studies .................................. 17
VIII.C.3. Impact on the risk management system ......................................................... 18
VIII.C.4. Regulatory supervision of non-interventional post-authorisation safety studies .... 18
VIII.C.4.1. Roles and responsibilities of the marketing authorisation holder ...................... 19
VIII.C.4.2. Roles and responsibilities of the PRAC and national competent authority .......... 20
VIII.C.4.3. Roles and responsibilities of the Agency ....................................................... 20
VIII.C.5. Changes to the marketing authorisation following results from a non-interventional
post-authorisation safety study................................................................................... 21
VIII.Appendix 1. Methods for post-authorisation safety studies ............... 23
Guideline on good pharmacovigilance practices (GVP) – Module VIII (Rev 1)
EMA/813938/2011 Rev 1 Page 4/27
VIII.A. Introduction
A post-authorisation safety study (PASS) is defined in Directive 2001/83/EC (DIR) Art 1(15) as any
study relating to an authorised medicinal product conducted with the aim of identifying, characterising
or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring
the effectiveness of risk management measures.
A PASS may be initiated, managed or financed by a marketing authorisation holder voluntarily, or
pursuant to an obligation imposed by a competent authority [DIR Art 107m(1), Regulation (EC) No
726/2004 (REG) Art 28b]. These studies shall be conducted in accordance with the following
provisions:
DIR Art 107m-q and Commission Implementing Regulation (EU) No 520/2012 (IR) Art 36-38
for PASS initiated, managed or financed by a marketing authorisation holder pursuant to an
obligation imposed by a competent authority; these studies include:
studies imposed as an obligation in accordance with REG Art 10 and Art 10a and with DIR
Art 21a and Art 22a (category 1 of studies in Module V);
studies imposed as a specific obligation in the framework of a marketing authorisation
granted under exceptional circumstances (category 2 of studies in Module V);
DIR Art 107m for PASS initiated, managed or financed by a marketing authorisation holder
voluntarily, namely those that have not been imposed as an obligation; they include those
required in the risk management plan (RMP) to investigate a safety concern or to evaluate the
effectiveness of risk minimisation activities (category 3 of studies in Module V) and, depending
on their objective (see VIII.B.3.), some studies that may provide safety information of less
significance (category 4 of studies of Module V).
This Module concerns PASS which are clinical trials or non-interventional studies and does not address
non-clinical safety studies.
A PASS is non-interventional if the following requirements are cumulatively fulfilled [Volume 10 of The
Rules Governing Medicinal Products in the European Union, Questions and Answers, Version 9.0,
August 2011, Question 1.9]1:
the medicinal product is prescribed in the usual manner in accordance with the terms of the
marketing authorisation;
the assignment of the patient to a particular therapeutic strategy is not decided in advance by
a trial protocol but falls within current practice and the prescription of the medicine is clearly
separated from the decision to include the patient in the study; and
no additional diagnostic or monitoring procedures are applied to the patients and
epidemiological methods are used for the analysis of collected data.
Non-interventional studies are defined by the methodological approach used and not by its scientific
objectives. Non-interventional studies include database research or review of records where all the
events of interest have already happened (this may include case-control, cross-sectional, cohort or
other study designs making secondary use of data). Non-interventional studies also include those
involving primary data collection (e.g. prospective observational studies and registries in which the
data collected derive from routine clinical care), provided that the conditions set out above are met. In
these studies, interviews, questionnaires and blood samples may be performed as part of normal
clinical practice.
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If a PASS is a clinical trial, the provisions of Directive 2001/20/EC and of Volume 10 of The Rules
Governing Medicinal Products in the European Union1 shall be followed.
The purposes of this Module are to:
provide general guidance for the transparency, scientific standards and quality standards of
non-interventional PASS conducted by marketing authorisation holders voluntarily or pursuant
to an obligation imposed by a competent authority (VIII.B.);
describe procedures whereby competent authorities may impose to a marketing authorisation
holder an obligation to conduct a clinical trial or a non-interventional study (VIII.C.2.), and the
impact of this obligation on the risk management system (VIII.C.3);
describe procedures that apply to non-interventional PASS imposed as an obligation for the
protocol oversight and reporting of results (VIII.C.4.) and for changes to the marketing
authorisation following results (VIII.C.5.).
In this Module, all applicable legal requirements are referenced in the way explained in the GVP
Introductory Cover Note and are usually identifiable by the modal verb “shall”. Guidance for the
implementation of legal requirements is provided using the modal verb “should”.
VIII.B. Structures and processes
VIII.B.1. Scope
The guidance in VIII.B. applies to non-interventional PASS which are initiated, managed or financed by
a marketing authorisation holder and conducted in the European Union (EU). This guidance should also
be used for studies conducted outside the EU which have been imposed or required by a EU competent
authority (categories 1, 2 and 3 of studies defined in Module V).
Where applicable, legal requirements which are applicable to studies conducted pursuant to an
obligation are recommended to studies conducted voluntarily in order to support the same level of
transparency, scientific standards and quality standards for all PASS. This applies, for example, to the
format of study protocols, abstracts and final study reports and to the communication of study
information to the Agency and national competent authorities. Where relevant, a distinction is made in
the text between situations where the provision of the guidance represents a legal requirement or a
recommendation.
This guidance apply to studies initiated, managed or financed by a marketing authorisation holder as
well as those conducted by a third party on behalf of the marketing authorisation holder.
This guidance applies to studies that involve primary collection of safety data directly from patients and
health care professionals and those that make secondary use of data previously collected from patients
and health care professionals for another purpose.
VIII.B.2. Terminology
Date at which a study commences: date of the start of data collection.
Start of data collection: the date from which information on the first study subject is first recorded in
the study dataset or, in the case of secondary use of data, the date from which data extraction starts
[IR Art 37]. Simple counts in a database to support the development of the study protocol, for
example to inform the sample size and statistical precision of the study, are not part of this definition.
1 http://ec.europa.eu/health/documents/eudralex/vol-10/
http://ec.europa.eu/health/documents/eudralex/vol-10/
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End of data collection: the date from which the analytical dataset is completely available [IR Art 37].
Analytical dataset: the minimum set of data required to perform the statistical analyses leading to the
results for the primary objective(s) of the study.
Substantial amendment to the study protocol: amendment to the protocol likely to have an impact on
the safety, physical or mental well-being of the study participants or that may affect the study results
and their interpretation, such as changes to the primary or secondary objectives of the study, to the
study population, to the sample size, to the definitions of the main exposure, outcome and
confounding variables and to the analytical plan.
VIII.B.3. Principles
In accordance with DIR Art 1(15), a post-authorisation study should be classified as a PASS when the
main aim for initiating the study includes any of the following objectives:
to quantify potential or identified risks, e.g. to characterise the incidence rate, estimate the
rate ratio or rate difference in comparison to a non-exposed population or a population
exposed to another drug or class of drugs, and investigate risk factors and effect modifiers;
to evaluate risks of a medicinal product used in patient populations for which safety
information is limited or missing (e.g. pregnant women, specific age groups, patients with renal
or hepatic impairment);
to evaluate the risks of a medicinal product after long-term use;
to provide evidence about the absence of risks;
to assess patterns of drug utilisation that add knowledge on the safety of the medicinal product
(e.g. indication, dosage, co-medication, medication errors);
to measure the effectiveness of a risk minimisation activity.
Whereas the PASS design should be appropriate to address the study objective(s), the classification of
a post-authorisation study as a PASS is not constrained by the type of design chosen if it fulfils the
criteria as set in DIR Art 1(15). For example, a systematic literature review or a meta-analysis may be
considered as PASS depending on their aim.
Relevant scientific guidance should be considered by marketing authorisation holders and investigators
for the development of study protocols, the conduct of studies and the writing of study reports, and by
the Pharmacovigilance Risk Assessment Committee (PRAC) and national competent authorities for the
evaluation of study protocols and study reports. Relevant scientific guidance includes the ENCePP
Guide on Methodological Standards in Pharmacoepidemiology, 2 the ENCePP Checklist for Study
Protocols2, the Guideline on Conduct of Pharmacovigilance for Medicines Used by the Paediatric
Population for studies conducted in children,3 and the Guidelines for Good Pharmacoepidemiology
Practices of the International Society of Pharmacoepidemiology (ISPE GPP)4.
For studies that are funded by a marketing authorisation holder, including studies developed,
conducted or analysed fully or partially by investigators who are not employees of the marketing
authorisation holder, the marketing authorisation holder should ensure that the investigators are
qualified by education, training and experience to perform their tasks. The research contract between
the marketing authorisation holder and investigators should ensure that the study meets its regulatory
2 http://www.encepp.eu/standards_and_guidances/index.html
3 EMEA/CHMP/PhVWP/235910/2005; available on
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003764.pdf
4 http://www.pharmacoepi.org/resources/guidelines_08027.cfm
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003764.pdf
http://www.pharmacoepi.org/resources/guidelines_08027.cfm
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obligations while permitting their scientific expertise to be exercised throughout the research process.
In the research contract, the marketing authorisation holder should consider the provisions of the
ENCePP Code of Conduct,5 and address the following aspects:
rationale, main objectives and brief description of the intended methods of the research to be
carried out by the investigator(s);
rights and obligations of the investigator(s) and marketing authorisation holder;
clear assignment of tasks and responsibilities;
procedure for achieving agreement on the study protocol;
provisions for meeting the marketing authorisation holder’s pharmacovigilance obligations,
including the reporting of adverse reactions and other safety data by investigators, where
applicable;
intellectual property rights arising from the study and access to study data;
storage and availability of analytical dataset and statistical programmes for audit and
inspection;
communication strategy for the scheduled progress and final reports;
publication strategy of interim and final results.
Non-interventional post-authorisation safety studies shall not be performed where the act of
conducting the study promotes the use of a medicinal product [DIR Art 107m(3)]. This requirement
applies to all studies and to all activities performed in the study, including for studies conducted by the
personnel of the marketing authorisation holder and by third parties on behalf of the marketing
authorisation holder.
Payments to healthcare professionals for participating shall be restricted to compensation for time and
expenses incurred [DIR Art 107m(4)].
VIII.B.4. Study registration
In order to support transparency on non-interventional PASS conducted voluntarily or pursuant an
obligation and to facilitate exchange of pharmacovigilance information between the Agency, Member
States and marketing authorisation holders, the marketing authorisation holder should make study
information (including for studies conducted outside the EU) available in the EU electronic register of
post-authorisation studies (EU PAS Register) maintained by the Agency and accessible through the
European medicines web-portal.6 The study protocol should be entered in the register before the start
of data collection. Updates of the study protocol in case of substantial amendments, progress reports
where applicable, and the final study report should be entered in the register (preferably within two
weeks after their finalisation). Study information should normally be submitted in English. If the study
protocol or the study report is written in another language, the marketing authorisation should
facilitate access to study information by including an English translation of the title, the abstract of the
study protocol and the abstract of the final study report.
Where prior publication of the protocol could threaten the validity of the study (for example, in a case-
control study where prior knowledge of the exposure of interest could lead to information bias) or the
protection of intellectual rights, a study protocol with redactions made by the MAH may be entered into
the register prior to the start of data collection. These redactions should be justified and kept to the
5 http://www.encepp.eu/code_of_conduct/index.html
6 http://www.encepp.eu/encepp_studies/indexRegister.shtml
http://www.encepp.eu/code_of_conduct/index.html
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minimum necessary for the objective aimed by the redaction process. Whenever a redacted study
protocol is published prior to the start of data collection, the title page of the protocol should include
the mention “Redacted protocol” and the complete study protocol should be made available to the
Agency and national competent authorities upon request. The complete study protocol should be
entered in the register (preferably within two weeks after the end of data collection).
VIII.B.5. Study protocol
All post-authorisation safety studies must have a written study protocol before the study commences.
The study should follow a scientifically sound protocol developed by individuals with appropriate
scientific background and experience. EU and, where present, national requirements shall be followed
for ensuring the well-being and rights of the participants [DIR Art 107m(2)]. The marketing
authorisation holder may be required by the national competent authority to submit the protocol to the
competent authorities of the Member States in which the study is conducted [DIR Art 107m(5)].
For PASS initiated by the marketing authorisation holder pursuant to an obligation, see VIII.C.4 for the
submission of the study protocol.
Member States’ requirements for transmission of the study protocol are specified in Module VIII
Addendum I. For PASS concerning centrally-authorised products, the study protocol should also be
transmitted to the Agency.
In order to ensure compliance of the marketing authorisation holder with its pharmacovigilance
obligations, the qualified person responsible for pharmacovigilance (QPPV) or his/her delegate (see
Module I) should be involved in the review and sign-off of study protocols conducted in the EU. Where
applicable, the marketing authorisation holder’s pharmacovigilance contact person at national level
should be informed of any study sponsored or conducted by the marketing authorisation holder in that
Member State and have access to the protocol.
VIII.B.5.1. Format and content of the study protocol
The study protocol should include the following information:
1. Title: informative title including a commonly used term indicating the study design and the
medicinal product, substance or drug class concerned, and a sub-title with a version identifier and
the date of the last version. If the study protocol has been registered in the EU PAS Register,
subsequent versions of the protocol should mention on the title page “EU PAS Register No:” with
the registration number.
2. Marketing authorisation holder: name and address of the marketing authorisation holder.
3. Responsible parties: names, titles, qualifications, addresses, and affiliations of all main
responsible parties, including the main author(s) of the protocol, the principal investigator, a
coordinating investigator for each country in which the study is to be performed and other relevant
study sites. A list of all collaborating institutions and investigators should be made available to the
Agency and national competent authorities upon request.
4. Abstract: stand-alone summary of the study protocol including the following sub-sections:
Title with subtitles including version and date of the protocol and name and affiliation of main
author
Rationale and background
Research question and objectives
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Study design
Population
Variables
Data sources
Study size
Data analysis
Milestones
5. Amendments and updates: any substantial amendment and update to the study protocol after
the start of data collection, including a justification for each amendment or update, dates of each
change and a reference to the section of the protocol where the change has been made.
6. Milestones: table with planned dates for the following milestones:
Start of data collection
End of data collection
Study progress report(s) as referred to in Article 107m(5) of Directive 2001/83/EC
Interim report(s) of study results, where applicable, in line with phases of data analyses
Final report of study results
Any other important timelines in the conduct of the study should be presented.
7. Rationale and background: short description of the safety hazard(s), the safety profile or the
risk management measures that led to the initiation or imposition of the study, and short critical
review of available published and unpublished data to explain gaps in knowledge that the study is
intended to fill. The review may encompass relevant animal and human experiments, clinical
studies, vital statistics and previous epidemiologic studies. The review should cite the findings of
similar studies, and the expected contribution of the current study.
8. Research question and objectives: research question that explains how the study will address
the issue which led to the study being initiated or imposed, and research objectives, including any
pre-specified hypotheses and main summary measures.
9. Research methods: description of the research methods, including:
9.1. Study design: overall research design and rationale for this choice.
9.2. Setting: study population defined in terms of persons, place, time period, and selection
criteria, including the rationale for any inclusion and exclusion criteria and their impact on
the number of subjects available for analysis. Where any sampling from a source population
is undertaken, description of the source population and details of sampling methods should
be provided. Where the study design is a systematic review or a meta-analysis, the criteria
for the selection and eligibility of studies should be explained.
9.3. Variables: outcomes, exposures and other variables including measured risk factors should
be addressed separately, including operational definitions; potential confounding variables
and effect modifiers should be specified.
9.4. Data sources: strategies and data sources for determining exposures, outcomes and all
other variables relevant to the study objectives, such as potential confounding variables and
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effect modifiers. Where the study will use an existing data source, such as electronic health
records, any information on the validity of the recording and coding of the data should be
reported. If data collection methods or instruments are tested in a pilot study, plans for the
pilot study should be presented. If a pilot study has already been performed, a summary of
the results should be reported. Involvement of any expert committees to validate diagnoses
should be stated. In case of a systematic review or meta-analysis, the search strategy and
processes and any methods for confirming data from investigators should be described.
9.5. Study size: any projected study size, precision sought for study estimates and any
calculation of the sample size that can minimally detect a pre-specified risk with a pre-
specified statistical precision.
9.6. Data management: data management and statistical programmes to be used in the study,
including procedures for data collection, retrieval and preparation.
9.7. Data analysis: the major steps that lead from raw data to a final result, including methods
used to correct inconsistencies or errors, impute values, modify raw data, categorise,
analyse and present results, and procedures to control sources of bias and their influence on
results; statistical procedures to be applied to the data to obtain point estimates and
confidence intervals of measures of occurrence or association, and sensitivity analyses.
9.8. Quality control: description of any mechanisms and procedures to ensure data quality and
integrity, including accuracy and legibility of collected data and original documents, extent of
source data verification and validation of endpoints, storage of records and archiving of
statistical programmes. As appropriate, certification and/or qualifications of any supporting
laboratory or research groups should be included.
9.9. Limitations of the research methods: any potential limitations of the study design, data
sources, and analytic methods, including issues relating to confounding, bias,
generalisability, and random error. The likely success of efforts taken to reduce errors
should be discussed.
10. Protection of human subjects: safeguards in order to comply with national and European Union
requirements for ensuring the well-being and rights of participants in non-interventional post-
authorisation safety studies.
11. Management and reporting of adverse events/adverse reactions: procedures for the
collection, management and reporting of individual cases of adverse reactions and of any new
information that might influence the evaluation of the benefit-risk balance of the product while the
study is being conducted. For studies where reporting is not required (see Module VI), this should
be stated.
12. Plans for disseminating and communicating study results, including any plans for
submission of progress reports and final reports.
13. References.
The format of the study protocol should follow the Guidance for the format and content of the protocol
of non-interventional post-authorisation safety studies published by the Agency7.
Feasibility studies that were carried out to support the development of the protocol, for example, the
testing of a questionnaire or simple counts of medical events or prescriptions in a database to
determine the statistical precision of the study, should be reported in the appropriate section of the
study protocol with a summary of their methods and results. The full report should be made available
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to the Agency and national competent authorities upon request. Feasibility studies that are part of the
research process should be described in the protocol, for example, a pilot evaluation of the study
questionnaire(s) used for the first set of patients recruited into the study.
An annex should list all separate documents and list or include any additional or complementary
information on specific aspects not previously addressed (e.g. questionnaires, case report forms), with
clear document references.
VIII.B.5.2. Substantial amendments to the study protocol
The study protocol should be amended and updated as needed throughout the course of the study.
Any substantial amendments to the protocol after the study start should be documented in the protocol
in a traceable and auditable way including the dates of the changes. If changes to the protocol lead to
the study being considered an interventional clinical trial, the national competent authorities and the
Agency should be informed immediately and the study shall subsequently be conducted in accordance
with Directive 2001/20/EC and Volume 10 of The Rules Governing Medicinal Products in the European
Union.
For PASS initiated by the marketing authorisation holder pursuant to an obligation, see VIII.C.4 for the
submission of substantial amendments to the study protocol.
Member States’ requirements for transmission of substantial amendments to the study protocol are
specified in Module VIII Addendum I. For PASS concerning centrally-authorised products, substantial
amendments to the study protocol should also be transmitted to the Agency.
VIII.B.6. Reporting of pharmacovigilance data to competent authorities
VIII.B.6.1. Data relevant to the risk-benefit balance of the product
The marketing authorisation holder shall monitor the data generated while the study is being
conducted and consider their implications for the risk-benefit balance of the medicinal product
concerned [DIR Art 107m(7)]. Any new information that may affect the risk-benefit balance of the
medicinal product should be communicated immediately in writing as an Emerging Safety Issue to
competent authorities of the Member States in which the product is authorised and to the Agency via
email (P-PV-emerging-safety-issue@ema.europa.eu). Information affecting the risk-benefit balance of
the medicinal product may include that arising from an analysis of adverse reactions and aggregated
data.
This communication should not affect information on the results of studies which should be provided by
means of periodic safety update reports (PSURs) (see Module VII) and in RMP updates (see Module V),
where applicable.
VIII.B.6.2. Reporting of adverse reactions/adverse events
Adverse reactions/adverse events should be reported to competent authorities in accordance with the
provisions of Module VI. Procedures for the collection, management (including a review by the
marketing authorisation holder if appropriate) and reporting of suspected adverse reactions/adverse
events should be put in place and summarised in the study protocol. If appropriate, reference can be
made to the Pharmacovigilance System Master File (see Module II) but details specific to the study
should be described in this section. For study designs where expedited reporting is not required, this
should be stated in the study protocol.
mailto:P-PV-emerging-safety-issue@ema.europa.eu
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VIII.B.6.3. Study reports
VIII.B.6.3.1 Progress reports
Progress reports may be requested by a national competent authority [DIR Art 107m(5)]. They may
also be requested by the PRAC, and by the Agency for PASS concerning centrally-authorised products.
Requests for progress reports may be made before the study commences or any time during the study
conduct. They may be guided by the communication of risk-benefit information arising from the study
or the need for information about the study progress in the context of regulatory procedures or
important safety communication about the product.
Upon request from a national competent authority, progress reports shall be submitted to the
competent authorities of the Member States in which the study is conducted [DIR Art 107m(5)].
Member States’ requirements for transmission of progress reports are specified in Module VIII
Addendum I. For PASS concerning centrally-authorised products, progress reports should also be
transmitted to the Agency.
The timing of the progress reports should be agreed with the relevant competent authorities and
specified in the study protocol when they have been agreed before the study commences. Study
progress should also be reported in any periodic safety update reports (PSURs) (see Module VII) and
risk management plan (RMP) updates (see Module V), where applicable.
The content of the progress report should follow a logical sequence and should include all the available
data that are judged relevant for the progress of the study, for example, number of patients who have
entered the study, number of exposed patients or number of patients presenting the outcome,
problems encountered and deviations from the expected plan. The progress report may also include
any interim report of study results. After review of the report, additional information may be
requested.
VIII.B.6.3.2. Final study report
The final study report should be submitted as soon as possible within 12 months of the end of data
collection.
For PASS initiated by the marketing authorisation holder pursuant to an obligation, see VIII.C.4 as
regards submission of the final study report.
Member States’ requirements for transmission of the final study report are specified in Module VIII
Addendum I. For PASS concerning centrally-authorised products, the final study report should also be
transmitted to the Agency.
If a study is discontinued, a final report should be submitted and the reasons for terminating the study
should be provided.
The final study report should include the following information:
1. Title: title including a commonly used term indicating the study design; sub-titles with date of final
report and name and affiliation of main author. If the study has been registered in the EU PAS
Register, the final study report should mention on the title page “EU PAS Register No:” with the
registration number.
2. Abstract: stand-alone summary in the format presented below.
3. Marketing authorisation holder: name and address of the marketing authorisation holder.
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4. Investigators: names, titles, degrees, addresses and affiliations of all main responsible parties,
including the main author(s) of the protocol, the principal investigator, a coordinating investigator
for each country in which the study is to be performed and other relevant study sites. A list of all
collaborating institutions and investigators should be made available to the Agency and national
competent authorities upon request.
5. Milestones: planned and actual dates for the following milestones:
Start of data collection
End of data collection or date of early termination, if applicable, with reasons for termination
Study progress report(s)
Interim report(s) of study results, where applicable
Final report of study results
Any other important milestone applicable to the study, including date of protocol approval by
an Institutional Review Board/Independent Ethics Committee if applicable, and date of study
registration in the EU PAS Register.
6. Rationale and background: short description of the safety concern(s) that led to the study being
initiated or imposed, and short critical review of relevant published and unpublished data
evaluating pertinent information and gaps in knowledge that the study is intended to fill.
7. Research question and objectives: research question and research objectives, including any
pre-specified hypotheses, as stated in the study protocol.
8. Amendments and updates to the protocol: list of any substantial amendment and update to
the initial study protocol after the start of data collection, including a justification for each
amendment or update.
9. Research methods:
9.1. Study design: key elements of the study design and the rationale for this choice.
9.2. Setting: setting, locations, and relevant dates for the study, including periods of
recruitment, follow-up, and data collection. In case of a systematic review or meta-analysis,
study characteristics used as criteria for eligibility, with rationale.
9.3. Subjects: any source population and eligibility criteria of study subjects. Sources and
methods of selection of participants should be provided, including, where relevant methods
for case ascertainment, as well as number of and reasons for dropouts.
9.4. Variables: all outcomes, exposures, predictors, potential confounders, and effect modifiers,
including operational definitions and diagnostic criteria, if applicable.
9.5. Data sources and measurement: for each variable of interest, sources of data and details
of methods of assessment and measurement. If the study has used an existing data source,
such as electronic health records, any information on the validity of the recording and
coding of the data should be reported. In case of a systematic review or meta-analysis,
description of all information sources, search strategy, methods for selecting studies,
methods of data extraction and any processes for obtaining or confirming data from
investigators.
9.6. Bias: any efforts to assess and address potential sources of bias.
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9.7. Study size: study size, rationale for any sample size calculation and any method for
attaining projected study size.
9.8. Data transformation: transformations, calculations or operations on the data, including
how quantitative data were handled in the analyses and which groupings were chosen and
why.
9.9. Statistical methods: description of:
main summary measures
statistical methods applied to the study, including those used to control for confounding
and, for meta-analyses, methods for combining results of studies
any methods used to examine subgroups and interactions
how missing data were addressed
any sensitivity analyses
any amendment to the plan of data analysis included in the study protocol, with a
rationale for the change.
9.10. Quality control: mechanisms to ensure data quality and integrity.
10. Results: presentation of tables, graphs, and illustrations to present the pertinent data and reflect
the analyses performed. Both unadjusted and adjusted results should be presented. Precision of
estimates should be quantified using confidence intervals. This section should include the following
sub-sections:
10.1. Participants: numbers of study subjects at each stage of study, e.g. numbers potentially
eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-
up, and analysed, and reasons for non-participation at any stage. In the case of a
systematic review or meta-analysis, number of studies screened, assessed for eligibility and
included in the review with reasons for exclusion at each stage.
10.2. Descriptive data: characteristics of study participants, information on exposures and
potential confounders and number of participants with missing data for each variable of
interest. In case of a systematic review or meta-analysis, characteristics of each study from
which data were extracted (e.g. study size, follow-up).
10.3. Outcome data: numbers of participants across categories of main outcomes.
10.4. Main results: unadjusted estimates and, if applicable, confounder-adjusted estimates and
their precision (e.g. 95% confidence interval). If relevant, estimates of relative risk should
be translated into absolute risk for a meaningful time period.
10.5. Other analyses: other analyses done, e.g. analyses of subgroups and interactions, and
sensitivity analyses.
10.6. Adverse events and adverse reactions: summary of all adverse events/adverse
reactions reported in the study, in line with requirements described in Module VI. For certain
study designs such as case-control or retrospective cohort studies, particularly those
involving electronic health care records, systematic reviews and meta-analyses where it is
not feasible to make a causality assessment at the individual case level, this should be
stated.
11. Discussion:
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11.1. Key results: key results with reference to the study objectives, prior research in support of
and conflicting with the findings of the completed post-authorisation safety study, and,
where relevant, impact of the results on the risk-benefit balance of the product.
11.2. Limitations: limitations of the study taking into account circumstances that may have
affected the quality or integrity of the data, limitations of the study approach and methods
used to address them (e.g., response rates, missing or incomplete data, imputations
applied), sources of potential bias and imprecision and validation of the events. Both
direction and magnitude of potential biases should be discussed.
11.3. Interpretation: interpretation of results considering objectives, limitations, multiplicity of
analyses, results from similar studies and other relevant evidence.
11.4. Generalisability: the generalisability (external validity) of the study results.
12. References.
13. Other information: any additional or complementary information on specific aspects not
previously addressed.
The format of the final study report should follow the Guidance for the format and content of the final
study report of non-interventional post-authorisation safety studies published by the Agency8.
The abstract of the final study report should include a summary of the study methods and findings
presented in the following format:
1. Title, with subtitles including date of the abstract and name and affiliation of main author;
2. Keywords (not more than five keywords indicating the main study characteristics);
3. Rationale and background;
4. Research question and objectives;
5. Study design;
6. Setting;
7. Subjects and study size, including dropouts;
8. Variables and data sources;
9. Results;
10. Discussion (including, where relevant, an evaluation of the impact of study results on the risk-
benefit balance of the product);
11. Marketing authorisation holder;
12. Names and affiliations of principal investigators.
VIII.B.7. Publication of study results
For studies that are fully or partially conducted by investigators who are not employees of the
marketing authorisation holder, the marketing authorisation holder and the investigator should agree
in advance a publication policy allowing the principal investigator to independently prepare publications
based on the study results irrespective of data ownership. The marketing authorisation holder should
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be entitled to view the results and interpretations included in the manuscript and provide comments
prior to submission of the manuscript for publication.
VIII.B.7.1. Regulatory submission of manuscripts accepted for publication
In order to allow national competent authorities to review in advance the results and interpretations to
be published, the marketing authorisation holder should communicate to the Agency and the
competent authorities of the Member States in which the product is authorised the final manuscript of
the article within two weeks after first acceptance for publication.
VIII.B.8. Data protection
Marketing authorisation holders and investigators shall follow relevant national legislation and guidance
of those Member States where the study is being conducted [DIR Art 107m(2)]. The legislation on data
protection must be followed in accordance with Directive 95/46/EC of the European Parliament and of
the Council on the protection of individuals with regard to the processing of personal data and on the
free movement of such data.
For PASS imposed as an obligation, the marketing authorisation holder shall ensure that all study
information is handled and stored so as to allow for accurate reporting, interpretation and verification
of that information and shall ensure that the confidentiality of the records of the study subjects
remains protected [IR Art 36]. This provision should also be applied to PASS voluntarily initiated,
managed or financed by the marketing authorisation holder.
VIII.B.9. Quality systems, audits and inspections
The marketing authorisation holder shall ensure the fulfilment of its pharmacovigilance obligations in
relation to the study and that this can be audited, inspected and verified. For PASS imposed as an
obligation, the marketing authorisation holder shall ensure that the analytical dataset and statistical
programmes used for generating the data included in the final study report are kept in electronic
format and are available for auditing and inspection [IR Art 36]. This provision should also be applied
to PASS voluntarily initiated, managed or financed by the marketing authorisation holder.
VIII.B.10. Impact on the risk management system
Non-interventional PASS imposed as an obligation or required to investigate a safety concern of the
RMP (category 3 of studies in Module V) should be described in the RMP Part III (see Module V).
Protocols for studies in the pharmacovigilance plan should be provided in RMP annex 6 until submission
of the final study report to the competent authorities Studies looking at the effectiveness of risk
minimisation measures should be included in the pharmacovigilance plan against the specific safety
concern(s) as well as described in detail in the risk minimisation plan.
Other non-interventional PASS which are not obligations or required studies in the RMP but which could
provide relevant information on the safety profile of the product (category 4 of studies in Module V)
should be listed in the RMP section III “Summary table of additional pharmacovigilance activities.
For studies imposed as an obligation, see also VIII.C.3.
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VIII.C. Operation of the EU network
VIII.C.1. Scope
Provisions of VIII.C. refer specifically to post-authorisation safety studies initiated, managed or
financed by marketing authorisation holders pursuant to obligations imposed by a competent authority.
Sections VIII.C.2. and VIII.C.3. apply to both interventional and non-interventional PASS. Sections
VIII.C.4. and VIII.C.5. apply to non-interventional PASS.
VIII.C.2. Procedure for imposing post-authorisation safety studies
In the EU, the conduct of any post-authorisation safety study (PASS) can be imposed during the
evaluation of the initial marketing authorisation application or during the post-authorisation phase by
the Agency or the national competent authority whenever there are concerns about the risks of an
authorised medicinal product. This obligation shall be duly justified based on benefit-risk
considerations, shall be notified in writing and shall include the objectives and timeframe for the
submission and conduct of the study [DIR Art 22a, REG Art 10a]. The request may also include
recommendations on key elements of the study (e.g. study design, setting, exposure(s), outcome(s),
study population). An overview of study designs and databases frequently used in post-authorisation
safety studies is provided in VIII.Appendix 1.
a. Request for a post-authorisation safety study as part of the initial marketing
authorisation application
A marketing authorisation may be granted by the competent authority subject to the conduct of a
PASS [DIR Art 21a, REG Art 10]. If the need for a PASS is identified for a centrally authorised product
or a nationally authorised product authorised through the mutual recognition or the decentralised
procedure, the PRAC may adopt an advice with an assessment report to the Committee for Medicinal
Products for Human Use (CHMP) or to the Coordination Group for Mutual Recognition and Decentralised
Procedures - Human (CMDh) as applicable.
b. Request for a post-authorisation safety study during a post-authorisation regulatory
procedure
The need for a PASS could be identified by the Agency or a national competent authority during a post-
authorisation regulatory procedure, for example, an extension or a variation to a marketing
authorisation or a renewal procedure. If the need for a PASS is identified for a centrally authorised
product or a nationally authorised product through the mutual recognition or the decentralised
procedure, the PRAC may adopt an advice with an assessment report to the CHMP or the CMDh as
applicable.
c. Request for a post-authorisation safety study due to an emerging safety concern
After the granting of the marketing authorisation, the Agency or a national competent authority, where
applicable, may impose on the marketing authorisation holder an obligation to conduct a post-
authorisation safety study if there are concerns about the risk of the authorised medicinal product [DIR
Art 22a, REG Art 10a], for example following evaluation of a safety signal (see Module IX). If the need
for a PASS is identified for a centrally authorised product or a nationally authorised product through
the mutual recognition or the decentralised procedure, the PRAC may adopt an advice with an
assessment report to the CHMP or the CMDh as applicable.
d. Joint post-authorisation safety studies
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If safety concerns apply to more than one medicinal product, the Agency or the national competent
authority shall, following consultation with the PRAC, encourage the marketing authorisation holders
concerned to conduct a joint PASS [DIR Art 22a, REG Art 10a]. A joint PASS may also be necessary
where there are limited patients (rare diseases) or the adverse reaction is rare. Requests to the
marketing authorisation holders should contain the justification for the request of a joint study and the
elements of the study design that support a joint protocol. Upon request from the marketing
authorisation holders, the national competent authority or the Agency may organise a pre-submission
meeting in order to provide suggestions for a joint study proposal and facilitate agreement in
developing a joint protocol. If a joint protocol is not voluntarily agreed and different proposals are
submitted, the national competent authority or Agency may define, in consultation with the PRAC,
either a common core protocol or key elements (for example, the study design, the study population
and the definition of exposure and outcomes) which each marketing authorisation holder will have to
implement in the study protocol to be submitted to the national competent authority or the PRAC in
accordance with DIR Art 107n(1).
e. Written observations in response to the imposition of an obligation
Within 30 days of receipt of the written notification of the obligation, the marketing authorisation
holder may request the opportunity to present written observations in response to the imposition of
the obligation [DIR Art 22a(2), REG Art 10a(2)]. The national competent authority or the Agency shall
specify a time limit for the provision of these observations. On the basis of the written observations
submitted by the marketing authorisation holder, the national competent authority or the European
Commission shall withdraw or confirm the obligation. When the obligation is confirmed, the marketing
authorisation shall be subject to variation to include the obligation as a condition and the risk
management plan (RMP), where applicable, shall be updated accordingly [DIR Art 22a(3), REG Art
10a(3)] (see Module V).
VIII.C.3. Impact on the risk management system
All post-authorisation safety studies imposed as a condition to the marketing authorisation will be
described in the RMP (see Module V and VIII.B.10.) and their results provided in the PSUR following
completion of the final report, where applicable (see Module VII).
All relevant sections/modules of the RMP should be amended to document the conduct of the study,
including the safety specification, the pharmacovigilance plan, the risk minimisation plan and the
summary of activities, as appropriate. A copy of the study protocol approved by the competent
authority should be provided annex 6 of the RMP.
When a RMP does not exist, a new RMP should be developed referring to the post-authorisation safety
study.
VIII.C.4. Regulatory supervision of non-interventional post-authorisation
safety studies
Non-interventional PASS conducted pursuant to obligations imposed by a competent authority are
supervised and assessed by the PRAC, unless the PASS was requested by a national competent
authority of a single Member State according to DIR Art 22a and conducted only in that Member State,
in which case national oversight procedures apply [DIR Art 107n(1)].
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VIII.C.4.1. Roles and responsibilities of the marketing authorisation holder
Following the imposing of the obligation to conduct a non-interventional PASS as a condition to the
marketing authorisation, the marketing authorisation holder shall develop a study protocol and submit
it to the national competent authority or the PRAC for review [DIR Art 107n(1)] as appropriate. When
the PRAC is involved in the oversight of the study, the marketing authorisation holder shall submit the
study protocol to the PRAC and to the Agency.
The marketing authorisation holder has the responsibility to ensure that the study is not a clinical trial,
in which case Directive 2001/20/EC shall apply. If the study is a non-interventional study (see VIII.A.),
the marketing authorisation holder shall ensure that the study meets the requirements applicable to
non-interventional PASS set out in DIR Art 107m-q, in IR Art 36-38, in Module VIII.B and in
requirements specific to the requested PASS. The marketing authorisation holder shall ensure the
fulfilment of its pharmacovigilance obligations in relation to the study and that this can be audited,
inspected and verified (see VIII.B.8. and VIII.B.9.).
The marketing authorisation holder shall develop the study protocol following the format of IR Art 38
and should consider the recommendations set out in VIII.B.5.1. The study may commence only when
the written endorsement from the national competent authority or the PRAC, as appropriate, has been
issued. When a letter of endorsement has been issued by the PRAC, the marketing authorisation holder
shall forward the protocol to the competent authority of the Member State(s) in which the study is to
be conducted and may thereafter commence the study according to the endorsed protocol [DIR Art
107n(3)]. EU and national requirements shall be followed to ensure the well-being and rights of
participants in the study [DIR Art 107m(2)].
Prior to submission of the protocol, the marketing authorisation holder may submit a request to the
Agency for a pre-submission meeting with the Agency and the PRAC rapporteur in order to clarify
specific aspects of the requested study (such as study objectives, study population, definition of
exposure and outcomes) and to facilitate the development of the protocol in accordance with the
objectives determined by the PRAC.
After a study has been commenced, the marketing authorisation holder shall submit any substantial
amendments to the protocol, before their implementation, to the national competent authority or to
the PRAC, as appropriate (see VIII.B.2. for the definition of a substantial amendment). When the PRAC
is involved in the oversight of the study, the marketing authorisation holder shall submit the amended
study protocol to the PRAC and to the Agency.
The marketing authorisation holder may be requested to submit the study progress reports to the
competent authorities in which the study is conducted [DIR Art 107m(5)].
Upon completion of the study, the marketing authorisation holder shall submit a final study report,
including a public abstract, to the national competent authority or to the PRAC as soon as possible and
not later than 12 months after the end of data collection, unless a written waiver has been granted by
the national competent authority or the PRAC, as appropriate [DIR Art 107p(1)]. The final study report
shall follow the format of IR Art 38, with consideration to the recommendations set out in VIII.B.6.3.2.
The public abstract shall follow the format of IM Art 38.
When the PRAC is involved in the oversight of the study, the marketing authorisation holder shall
submit the final study report to the PRAC and to the Agency. When the PRAC is responsible for
regulatory supervision of the PASS, the marketing authorisation holder should request the waiver in
writing to the Agency at least three months before the due date for the submission of the report. The
request should include a justification for the waiver. The request should be assessed by the PRAC
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rapporteur and granted or rejected by the PRAC on the basis of the justification and timeline submitted
by the marketing authorisation holder.
The marketing authorisation holder shall submit the study protocol, the abstract of the final study
report and the final study report in English except for studies to be conducted in only one Member
State that requests the study according to DIR Art 22a. For the latter studies, the marketing
authorisation holder shall provide an English translation of the title and abstract of the study protocol
as well as an English translation of the abstract of the final study report [IR Art 36].
VIII.C.4.2. Roles and responsibilities of the PRAC and national competent
authority
When the PRAC is involved in the oversight of the study, the PRAC will nominate a PRAC rapporteur
responsible for the supervision of the PASS. The PRAC rapporteur should write a protocol assessment
report, including a list of questions if appropriate, and submit it for review and approval by the PRAC.
If the study proves to be interventional, the PRAC rapporteur should not provide an assessment report
but should issue an explanatory statement to the marketing authorisation holder that the study is a
clinical trial falling under the scope of Directive 2001/20/EC.
Within 60 days from submission of the draft protocol, the national competent authority or the PRAC
shall issue a letter endorsing the draft protocol, a letter of objection or a letter notifying the marketing
authorisation holder that the study is a clinical trial falling under the scope of Directive 2001/20/EC.
The letter of objection shall set out in detail the grounds for the objection in any of the following cases:
it is considered that the conduct of the study promotes the use of a medicinal product;
it is considered that the design of the study does not fulfil the study objectives [DIR Art
107n(2)].
In case of submission of an amended study protocol, the national competent authority or the PRAC, as
appropriate, shall assess the amendments and inform the marketing authorisation holder of its
endorsement or objection [DIR Art 107o]. The PRAC will provide the marketing authorisation holder
with a letter of endorsement or objection to the protocol amendment within 30 days of submission.
The letter of objection will provide a timeline by which the marketing authorisation holder should
resubmit an amended version of the protocol.
In cases where the PRAC has assessed the final study results, the PRAC will produce an assessment
report, including a list of questions as appropriate. If the PRAC addresses a list of questions to the
marketing authorisation holder, the PRAC conclusion on the study results, including their
recommendations to the CHMP or CMDh, as applicable (see VIII.C.5.), will be issued once the
marketing authorisation holder has addressed the questions posed.
VIII.C.4.3. Roles and responsibilities of the Agency
The Agency shall provide scientific secretariat to the PRAC.
Upon receipt of the study protocol and of the final study report submitted by the marketing
authorisation holder the Agency will provide the PRAC rapporteur with a summary of the study protocol
and of the final study report.
The Agency will inform the marketing authorisation holder in writing and within the appropriate
timelines of the decisions of the PRAC with respect to the assessment of the following:
Study protocol;
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Study protocol amendments;
Final study report;
Waiver request for the submission of the final study protocol.
When the marketing authorisation holder submit a request to the Agency for a pre-submission meeting
the Agency will be responsible for a timely set up of the meeting with the Agency and the PRAC
rapporteur.
The Agency shall make public on the European medicines web-portal protocols and public abstracts of
results of the post-authorisation safety studies referred to in DIR Art 107n and 107p.
VIII.C.5. Changes to the marketing authorisation following results from a
non-interventional post-authorisation safety study
The marketing authorisation holder shall evaluate whether the study results have an impact on the
marketing authorisation and shall, if necessary, submit to the national competent authorities or the
Agency an application to vary the marketing authorisation [DIR Art 107p(2)]. In such case, the
variation should be submitted to the national competent authority or the Agency with the final study
report within 12 months of the end of data collection. Where applicable, the PRAC and the CHMP or the
CMDh will coordinate the assessment of the study results within the variation procedure.
Following the review of the final study report, the PRAC may recommend variation, suspension or
revocation of the marketing authorisation [DIR Art 107q(2), REG Art 28b(2)]. The recommendation by
the PRAC shall mention any divergent positions and the grounds on which they are based [DIR Art
107q(1)].
For centrally authorised products, or substances for which at least one centrally-authorised product
exists, recommendations for the variation, suspension or revocation of the marketing authorisation
made by the PRAC shall be transmitted to the CHMP which shall adopt an opinion taking into account
the recommendation. The CHMP opinion shall be transmitted to the European Commission. The
Commission shall adopt a decision in accordance with REG Art 10. When the opinion of the CHMP
differs from the recommendation of the PRAC, the CHMP shall attach to its opinion a detailed
explanation [REG Art 28b(2)].
For nationally authorised products including those authorised through the mutual recognition or the
decentralised procedure and for substances where no centrally-authorised product exists, the Member
States represented within the CMDh shall agree a position taking into account the PRAC
recommendation and include a timetable for the implementation of this agreed position. When a
consensus agreement is reached, the chairman of the CMDh shall record the agreement and send the
agreed position to the marketing authorisation holder and Member States who should adopt necessary
measures to vary, suspend or revoke the marketing authorisation in line with the implementation
timetable of the CMDh. In case a variation is agreed upon, the marketing authorisation holder shall
submit to the national competent authorities an appropriate application for a variation, including an
updated summary of product characteristics (SmPC) and package leaflet within the determined
timetable for implementation. In case a consensus agreement cannot be reached, the position of the
majority of the Member States represented within the CMDh should be forwarded to the Commission
who shall apply the procedure laid down in DIR Art 33 and 34. Where the agreement reached by the
Member States represented within the CMDh or the position of the majority of Member States differs
from the recommendation of the PRAC, the CMDh shall attach to the agreement or majority position a
detailed explanation of the scientific grounds for differences together with the recommendation [DIR
Art 107q(2)].
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More urgent action may be required in certain circumstances, for example, based on interim results
included in progress reports (see also VIII.B.6.3.1).
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VIII.Appendix 1. Methods for post-authorisation safety
studies
VIII.App1.1. Study designs
Post-authorisation safety studies may adopt different designs depending on their objectives. A brief
description of the main types of studies, as well as the types of data resources available, is provided
hereafter. However, this Appendix is not intended to be exhaustive and should be complemented with
other information sources, such as the ENCePP Guide for Methodological Standards.
VIII.App1.1.1. Active surveillance
Active surveillance, in contrast to passive surveillance, seeks to ascertain more completely the number
of adverse events in a given population via a continuous organised process. An example of active
surveillance is the follow-up of patients treated with a particular medicinal product through a risk
management system. Patients who fill a prescription for this product may be asked to complete a brief
survey form and give permission for later contact. In general, it is more feasible to get comprehensive
data on individual adverse event reports through an active surveillance system than through a passive
reporting system. Automatic detection of abnormal laboratory values from computerised laboratory
reports in certain clinical settings may also provide an efficient active surveillance system.
VIII.App1.1.1.1. Intensive monitoring schemes
Intensive monitoring is a system of record collation in designated areas, e.g. hospital units or by
specific healthcare professionals in community practice. In such cases, the data collection may be
undertaken by monitors who attend ward rounds, where they gather information concerning
undesirable or unintended events thought by the attending physician to be causally related to the
medication. Monitoring may also be focused on certain major events that tend to be drug-related such
as jaundice, renal failure, haematological disorders, bleeding. The major strength of such systems is
that the monitors may document important information about the events and exposure to medicinal
products. The major limitation is the need to maintain a trained monitoring team over time.
Intensive monitoring may be achieved by reviewing medical records or interviewing patients and/or
physicians/pharmacists in a sample of sentinel sites to ensure complete and accurate data on reported
adverse events. The selected sites may provide information, such as data from specific patient
subgroups that would not be available in a passive spontaneous reporting system. Further, collection of
information on the use of a medicinal product, such as the potential for abuse, may be targeted at
selected sentinel sites. Some of the major weaknesses of sentinel sites are problems with selection
bias, small numbers of patients, and increased costs. Intensive monitoring with sentinel sites is most
efficient for those medicinal products used mainly in institutional settings such as hospitals, nursing
homes, and haemodialysis centres. Institutional settings may have a greater frequency of use for
certain products and may provide an infrastructure for dedicated reporting. In addition, automatic
detection of abnormal laboratory values from computerised laboratory reports in certain clinical
settings may provide an efficient active surveillance system.
VIII.App1.1.1.2. Prescription event monitoring
In prescription event monitoring, patients may be identified from electronic prescription data or
automated health insurance claims. A follow-up questionnaire can then be sent to each prescribing
physician or patient at pre-specified intervals to obtain outcome information. Information on patient
demographics, indication for treatment, duration of therapy (including start dates), dosage, clinical
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events, and reasons for discontinuation can be included in the questionnaire [VIII.App 1. References 6-
7]. Limitations of prescription event monitoring include incomplete physician response and limited
scope to study products which are used exclusively in hospitals. More detailed information on adverse
events from a large number of physicians and/or patients may be collected.
VIII.App1.1.1.3. Registries
A registry is an organised system that uses observational methods to collect uniform data on specified
outcomes in a population defined by a particular disease, condition or exposure. A registry can be used
as a data source within which studies can be performed. Entry in a registry is generally defined either
by diagnosis of a disease (disease registry) or prescription of a drug (exposure registry).
Disease/outcome registries, such as registries for blood dyscrasias, severe cutaneous reactions, or
congenital malformations may help collect data on drug exposure and other factors associated with a
clinical condition. A disease registry might also be used as a base for a case-control study comparing
the drug exposure of cases identified from the registry and controls selected from either patients within
the registry with another condition or from outside the registry, or for a case-only design (see VIII.App
1.1.2.4.).
Exposure registries address populations exposed to medicinal products of interest (e.g. registry of
rheumatoid arthritis patients exposed to biological therapies) to determine if a medicinal product has a
special impact on this group of patients. Some exposure registries address exposures to medicinal
products in specific populations, such as pregnant women. Patients may be followed over time and
included in a cohort study to collect data on adverse events using standardised questionnaires. Simple
cohort studies may measure incidence, but, without a comparison group, cannot evaluate any
association between exposures and outcomes. Nonetheless, they may be useful for signal amplification
particularly for rare outcomes. This type of registry may be very valuable when examining the safety of
an orphan drug indicated for a specific condition.
VIII.App1.1.2. Observational studies
Traditional epidemiological methods are a key component in the evaluation of adverse events. There
are a number of observational study designs that are useful in validating signals from spontaneous
reports, active surveillance programmes or case series. Major types of these designs are cross-
sectional studies, case-control studies, and cohort studies, based on primary data collection or
secondary use of existing data.
VIII.App1.1.2.1. Cross-sectional study (survey)
Data collected on a population of patients at a single point in time (or interval of time) regardless of
exposure or disease status constitute a cross-sectional study. These types of studies are primarily used
to gather data for surveys or for ecological analyses. A drawback of cross-sectional studies is that the
temporal relationship between exposure and outcome cannot be directly addressed, which limits its use
for etiologic research unless the exposures do not change over time. These studies are best used to
examine the prevalence of a disease at one time-point or to examine trends over time, when data for
serial time-points can be captured. These studies may also be used to examine the crude association
between exposure and outcome in ecologic analyses.
VIII.App1.1.2.2. Cohort Study
In a cohort study, a population-at-risk for an event of interest is followed over time for the occurrence
of that event. Information on exposure status is known throughout the follow-up period for each
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patient. A patient might be exposed to a medicinal product at one time during follow-up, but non-
exposed at another time point. Since the population exposure during follow-up is known, incidence
rates can be calculated. In many cohort studies involving exposure to medicinal product(s),
comparison cohorts of interest are selected on the basis of medication use and followed over time.
Cohort studies are useful when there is a need to know the incidence rates of adverse events in
addition to the relative risks of adverse events. Multiple adverse events may also be investigated using
the same data source in a cohort study. However, it may be difficult to recruit sufficient numbers of
patients who are exposed to a product of interest (such as an orphan drug) or to study very rare
outcomes. The identification of patients for cohort studies may come from large automated databases
or from data collected specifically for the study at hand. In addition, cohort studies may be used to
examine safety concerns in special populations (the elderly, children, patients with co-morbid
conditions, pregnant women) through over-sampling of these patients or by stratifying the cohort if
sufficient numbers of patients exist.
VIII.App1.1.2.3. Case-control study
In a case-control study, cases of disease (or events) are identified and patients without the disease or
event of interest at the time of selection, are then selected as controls from the source population that
gave rise to the cases. The exposure status of the two groups is then compared using the odds ratio,
which is an estimate of the relative risk of disease among the exposed as compared to the non-
exposed. Patients may be identified from an existing database or using data collected specifically for
the purpose of the study of interest. If safety information is sought for special populations, the cases
and controls may be stratified according to the population of interest (the elderly, children, pregnant
women, etc.). Existing large population-based databases are a useful and efficient means of providing
needed exposure and medical outcome data in a relatively short period of time. Case-control studies
are particularly useful when the goal is to investigate whether there is an association between a
medicinal product (or products) and one specific rare adverse event, as well as to identify risk factors
for adverse events (or actually, effect-modifiers). Risk factors may include conditions such as renal and
hepatic dysfunction, which might modify the relationship between the drug exposure and the adverse
event. Under specific conditions, a case-control study may also provide the absolute incidence rate of
the event. If all cases of interest (or a well-defined fraction of cases) in the catchment area are
captured and the fraction of controls from the source population is known, an incidence rate can be
calculated.
When the source population for the case-control study is a well-defined cohort, it is then possible to
select a random sample from it to form the control series. The name “nested case-control study” has
been coined to designate those studies in which the control sampling is density-based (e.g. the control
series represents the person-time distribution of exposure in the source population). The case-cohort is
also a variant in which the control sampling is performed on those persons who make up the source
population regardless of the duration of time they may have contributed to it.
A case-control approach could also be set up as a permanent scheme to identify and quantify risks
(case-control surveillance). This strategy has been followed for rare diseases with a relevant aetiology
fraction attributed to medicinal products, including blood dyscrasias or serious skin disorders.
VIII.App1.1.2.4. Other designs
Other designs have been proposed to assess the association between intermittent exposures and
short-term events, including the self-controlled case-series, the case-crossover and the case-time-
control studies. In these designs, only cases are used and the control information is obtained from past
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person-time experience of the cases themselves. One of the important strengths of these designs is
that those confounding variables that do not change within individuals are automatically matched.
VIII.App1.1.3. Clinical trials
When significant risks are identified from pre-approval clinical trials, further clinical trials might be
called for to evaluate the mechanism of action for the adverse reaction. If the study is a clinical trial,
provisions of Directive 2001/20/EC shall apply. In some instances, pharmacodynamic and
pharmacokinetic studies might be conducted to determine whether a particular dosing instruction can
put patients at an increased risk of adverse events. Genetic testing may also provide clues about which
group of patients might be at an increased risk of adverse reactions. Furthermore, based on the
pharmacological properties and the expected use of the medicinal product in general practice,
conducting specific studies to investigate potential drug-drug interactions and food-drug interactions
might be called for. These studies may include population pharmacokinetic studies and drug
concentration monitoring in patients and normal volunteers.
Sometimes, potential risks or unforeseen benefits in special populations might be identified from pre-
approval clinical trials, but cannot be fully quantified due to small sample sizes or the exclusion of
subpopulations of patients from these clinical studies. These populations might include the elderly,
children, or patients with renal or hepatic disorder. Children, the elderly, and patients with co-morbid
conditions might metabolise medicinal products differently than patients typically enrolled in clinical
trials. Further clinical trials might be used to determine and to quantify the magnitude of the risk (or
benefit) in such populations.
VIII.App1.1.3.1. Large simple trials
A large simple trial is a specific form of clinical trial where large numbers of patients are randomised to
treatment but data collection and monitoring is kept to the minimum, consistent with the aims of the
study. This design may be used in pharmacovigilance to elucidate the risk-benefit profile of a medicinal
product outside of the formal/traditional clinical trial setting and/or to fully quantify the risk of a critical
but relatively rare adverse event. The use of the term ‘simple’ refers to data structure and not data
collection. It is used in relation to situations in which a small number of outcomes are measured and
the term may not adequately reflect the complexity of the studies undertaken. These studies qualify as
clinical trials.
VIII.App1.1.4. Drug utilisation studies
Drug utilisation studies (DUS) describe how a medicinal product is, prescribed and used in routine
clinical practice in large populations, including elderly patients, children, pregnant women or patients
with hepatic or renal dysfunction, who are often excluded by randomized clinical trials. Stratification by
age, gender, concomitant medication and other characteristics allows a comprehensive characterization
of treated patients, including the distribution of those factors that may influence clinical, social, and
economic outcomes. From these studies, denominator data may be derived for use in determining
rates of adverse reactions. DUS have been used to describe the effect of regulatory actions and media
attention on the use of medicinal products, as well as to develop estimates of the economic burden of
adverse reactions. DUS may be used to examine the relationship between recommended and actual
clinical practice. These studies may help to monitor use in everyday medical practice and medication
error and to determine whether a medicinal product has potential for abuse by examining whether
patients are taking escalating dose regimens or whether there is evidence of inappropriate repeat
prescribing.
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VIII.App1.2. Data sources
Pharmacoepidemiological studies may be performed using a variety of data sources. Traditionally, field
studies were required for retrieving the necessary data on exposure, outcomes, potential confounders
and other variables, through interview of appropriate subjects (e.g. patients, relatives) or by
consulting the paper-based medical records. However, the advent of automated healthcare databases
has remarkably increased the efficiency of pharmacoepidemiologic research. There are two main types
of automated databases, those that contain comprehensive medical information, including
prescriptions, diagnosis, referral letters and discharge reports, and those mainly created for
administrative purposes, which require a record-linkage between pharmacy claims and medical claims
databases. These datasets may include millions of patients and allow for large studies. They may not
have the detailed and accurate information needed for some research, such as validated diagnostic
information or laboratory data, and paper-based medical records should be consulted to ascertain and
validate test results and medical diagnoses. Depending on the outcome of interest, the validation may
require either a case-by-case approach or just the review of a random sample of cases. Other key
aspects may require validation where appropriate. There are many databases in place for potential use
in pharmacoepidemiological studies or in their validation phase.
Marketing authorisation holders should select the best data source according to validity
(e.g. completeness of relevant information, possibility of outcome validation) and efficiency criteria
(e.g. time span to provide results). External validity should also be taken into account. As far as
feasible the data source chosen to perform the study should include the population in which the safety
concern has been raised. In case another population is involved, the marketing authorisation holder
should evaluate the differences that may exist in the relevant variables (e.g. age, sex, pattern of use
of the medicinal product) and the potential impact on the results. In the statistical analysis, the
potential effect of modification of such variables should be explored.
With any data source used, the privacy and confidentiality regulations that apply to personal data
should be followed.
29.07.2014
Datei
PD
See websites for contact details
European Medicines Agency www.ema.europa.eu
Heads of Medicines Agencies www.hma.eu
The European Medicines Agency is
an agency of the European Union
© European Medicines Agency and Heads of Medicines Agencies, 2012.
Reproduction is authorised provided the source is acknowledged.
22 June 2012
EMA/827661/2011
Guideline on good pharmacovigilance practices (GVP)
Module IX – Signal management
Draft finalised by the Agency in collaboration with Member States and
submitted to ERMS FG
19 January 2012
Draft agreed by ERMS FG 24 January 2012
Draft adopted by Executive Director 20 February 2012
Released for consultation 21 February 2012
End of consultation (deadline for comments) 18 April 2012
Revised draft finalised by the Agency in collaboration with Member
States
20 June 2012
Revised draft agreed by ERMS FG 21 June 2012
Revised draft adopted by Executive Director as final 22 June 2012
Date for coming into effect 2 July 2012
Guideline on good pharmacovigilance practices (GVP) – Module IX
EMA/827661/2011 Page 2/17
Table of contents
IX.A. Introduction ....................................................................................... 3
IX.B. Structures and processes.................................................................... 4
IX.B.1. Sources of data and information ........................................................................ 4
IX.B.2. Methodology for signal detection ........................................................................ 4
IX.B.3. The signal management process ........................................................................ 5
IX.B.3.1. Introduction.................................................................................................. 5
IX.B.3.2. Signal detection ............................................................................................ 5
IX.B.3.2.1. Review of individual case safety reports ........................................................ 6
IX.B.3.2.2. Statistical analyses ..................................................................................... 6
IX.B.3.2.3. Combination of statistical methods and review of individual case safety reports.. 7
IX.B.3.3. Signal validation ............................................................................................ 7
IX.B.3.4. Signal analysis and prioritisation ..................................................................... 8
IX.B.3.5. Signal assessment ......................................................................................... 9
IX.B.3.6. Recommendation for action ............................................................................ 9
IX.B.3.7. Exchange of information ............................................................................... 10
IX.B.4. Quality requirements ...................................................................................... 10
IX.B.4.1. Tracking ..................................................................................................... 10
IX.B.4.2. Quality systems and documentation .............................................................. 10
IX.C. Operation of the EU network ............................................................. 11
IX.C.1. Roles and responsibilities ................................................................................ 11
IX.C.1.1. Roles and responsibilities of the Agency ......................................................... 12
IX.C.1.2. Roles and responsibilities of the lead Member State ......................................... 13
IX.C.1.3. Roles and responsibilities of the national competent authorities ........................ 13
IX.C.1.4. Roles and responsibilities of the Pharmacovigilance Risk Assessment Committee . 14
IX.C.1.5. Roles and responsibilities of marketing authorisation holder.............................. 14
IX.C.2. Periodicity of data monitoring in EudraVigilance ................................................. 15
IX.C.3. Signal analysis, prioritisation and assessment by the Pharmacovigilance Risk
Assessment Committee (PRAC) .................................................................................. 16
IX.C.4. Processes for EU regulatory follow-up ............................................................... 16
IX.C.5. Record management in the EU regulatory network ............................................. 17
IX.C.6. Transparency ................................................................................................. 17
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IX.A. Introduction
The Report of the Council for International Organisations of Medical Sciences Working group VIII
Practical Aspects of Signal Detection in Pharmacovigilance (CIOMS, Geneva 2010) defines a signal as
information that arises from one or multiple sources (including observations and experiments), which
suggests a new potentially causal association, or a new aspect of a known association, between an
intervention and an event or set of related events, either adverse or beneficial, that is judged to be of
sufficient likelihood to justify verificatory action.
For the purpose of this Module, only new information related to adverse effects will be considered.
In order to suggest a new potentially causal association or a new aspect of a known association, any
signal should be validated taking into account other relevant sources of information.
The signal management process can be defined as the set of activities performed to determine
whether, based on an examination of individual case safety reports (ICSRs), aggregated data from
active surveillance systems or studies, literature information or other data sources, there are new risks
associated with an active substance or a medicinal product or whether known risks have changed. The
signal management process shall include all steps from initial signal detection; through their validation
and confirmation; analysis and prioritisation; and signal assessment to recommending action, as well
as the tracking of the steps taken and of any recommendations made [IR Art 21(1)].
In the European Union, the signal management process concerns all stakeholders involved in the
safety monitoring of medicinal products including patients, healthcare professionals, marketing
authorisation holders, regulatory authorities, scientific committees and decision-making bodies (such
as competent authorities in the Member States and the European Commission (EC)).
Whereas the EudraVigilance database will be a major source of pharmacovigilance information, the
signal management process covers signals arising from outside the EudraVigilance database or not
directly supported by the EudraVigilance database. For the purpose of monitoring data in
EudraVigilance database, only signals related to an adverse reaction shall be considered [IR Art 19(1)].
Regulation (EU) No 1235/2010 amending Regulation (EC) No 726/2004, Directive 2010/84/EU
amending Directive 2001/83/EC and Commission Implementing Regulation (EU) No 520/2012 on the
Performance of Pharmacovigilance Activities Provided for in Regulation (EC) No 726/2004 and Directive
2001/83/EC include provisions for signal management in the European Union.
In this Module, all applicable legal requirements are referenced as explained in the GVP Introductory
Cover Note and are usually identifiable by the modal verb “shall”. Guidance for the implementation of
legal requirements is provided using the modal verb “should”.
The objectives of this Module are:
• to provide general guidance and requirements on structures and processes involved in signal
management (section IX.B.);
• to describe how these structures and processes are applied in the setting of the EU
pharmacovigilance and regulatory network (section IX.C.).
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IX.B. Structures and processes
IX.B.1. Sources of data and information
The sources for identifying new signals are diverse. They potentially include all scientific information
concerning the use of medicinal products including quality, non-clinical, clinical, pharmacovigilance and
pharmacoepidemiological data. Specific sources for signals include spontaneous adverse drug reaction
(ADR) reporting systems, active surveillance systems, non-interventional studies, clinical trials,
scientific literature and other sources of information.
Signals from spontaneous reports may be detected from monitoring of individual case safety reports
(ICSRs), ADR databases, articles from the scientific literature or review of information provided by
marketing authorisation holders in the context of regulatory procedures (e.g. variations, renewals,
post-authorisation commitments, periodic safety update reports (PSURs), Risk Management Plan (RMP)
updates or from other activities related to the on-going benefit-risk monitoring of medicinal products.
Spontaneous reports of ADRs may also be notified to poison centres, teratology information services,
vaccine surveillance programmes, reporting systems established by marketing authorisation holders,
and any other structured and organised data collection schemes allowing patients and healthcare
professionals to report suspected adverse reactions related to medicinal products. Competent
authorities should liaise with other institutions or organisations managing such reporting system so as
to be informed of these suspected adverse reactions.
Due to the increase in volume of spontaneous reports of (ADRs), the introduction of electronic safety
reporting by patients and healthcare professionals and the mandatory electronic transmission of case
reports from marketing authorisation holders to competent authorities, signal detection is now
increasingly based on periodic monitoring of large databases such as the EudraVigilance database.
Signals may arise from a wide range of different study types, including quality, non-clinical,
interventional and non-interventional studies, systematic reviews and meta-analyses. Interventional
trials and observational studies may, by design, recruit and follow-up a defined population of subjects
who may experience ADRs. Review of aggregated data and statistical analyses may also point to an
elevated risk of an adverse event to be further investigated as a signal.
Published results of relevant studies should be identified by marketing authorisation holders by
screening the scientific literature. For general guidance on performing literature searches, refer to
Module VI.
Marketing authorisation holders should regularly screen internet or digital media under their
management or responsibility as specified in Module VI, for potential reports of suspected ADRs, which
may characterise a new signal. Marketing authorisation holders and competent authorities should seek
further information related to suspected ADRs they become aware of from any source. Suspected
serious ADRs should be confirmed if possible through other data sources such as EudraVigilance.
IX.B.2. Methodology for signal detection
As a general principle, signal detection should follow a recognised methodology, which may vary
depending on the type of medicinal product it is intended to cover. Vaccines may for example require
other methodological strategies.
The detection of signals shall be based on a multidisciplinary approach. Signal detection within the
EudraVigilance database shall be complemented by statistical analysis where appropriate [IR Art
19(2)].
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In order to determine the evidentiary value (i.e. the supporting evidence) of a signal a recognised
methodology shall be applied taking into account the clinical relevance, quantitative strength of the
association, the consistency of the data, the exposure-response relationship, the biological plausibility,
experimental findings, possible analogies and the nature and quality of the data [IR Art 20(1)].
Different factors may be taken into account for the prioritisation of signals, namely whether the
association or the active substance/medicinal product is new, the strength of the association, the
seriousness of the reaction involved and the documentation of the reports in the EudraVigilance
database [IR Art 20(2)].
IX.B.3. The signal management process
IX.B.3.1. Introduction
The signal management process covers all steps from detecting signals to recommending action(s) as
follows:
• signal detection;
• signal validation;
• signal analysis and prioritisation;
• signal assessment;
• recommendation for action;
• exchange of information.
Although these steps generally follow a logical sequence, the wide range of sources of information
available for signal detection may require some flexibility in the conduct of signal management e.g.:
• when signal detection is primarily based on a review of individual case safety reports (ICSRs), this
activity may include validation and preliminary prioritisation of any detected signal;
• when a signal is detected from results of a study, it is generally not possible or practical to assess
each individual case, and validation may require collection of additional data;
• recommendation for action (followed by decision in accordance with the applicable legislation) and
exchange of information are components to be considered at every step of the process.
For the purpose of this guidance, signals originating from the monitoring of data from spontaneous
reporting systems are considered as the starting point of the signal management process. The same
principles should apply for data originating from other sources.
IX.B.3.2. Signal detection
Detailed guidance on methods of signal detection may be found in the Report of CIOMS Working group
VIII Practical Aspects of Signal Detection in Pharmacovigilance (CIOMS, Geneva 2010) and in the
Guideline on the Use of Statistical Signal Detection Methods in the EudraVigilance Data Analysis
System (Doc. Ref. EMEA/106464/2006 rev. 1).
Whichever methods are employed for the detection of signals, the same principles should apply,
namely:
• the method used should be appropriate for the data set; for example, the use of complex statistical
tools may not be appropriate for smaller data sets;
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• data from all appropriate sources should be considered;
• systems should be in place to ensure the quality of the signal detection activity;
• any outputs from a review of cumulative data should be assessed by an appropriately qualified
person in a timely manner;
• the process should be adequately documented, including the rationale for the method and
periodicity of the signal detection activity.
Detection of signals may be performed based on a review of ICSRs, from statistical analyses in large
databases, or from a combination of both.
IX.B.3.2.1. Review of individual case safety reports
As specified in Module VI, ICSRs may originate from a spontaneous reporting system, post-
authorisation studies and monitoring of literature. Even a single report of a serious or severe adverse
reaction (for example, one case of toxic epidermal necrolysis, aplastic anaemia or liver transplant) may
be sufficient to raise a signal and to take further action. A review of ICSRs for this purpose should
consider the number of cases (after exclusion of duplicates), the patient’s demographics (including age
and gender), the suspected medicinal product (including dose administered, formulation) and the
suspected adverse reaction (including signs and symptoms), the temporal association, the clinical
outcome in relation to drug continuation or discontinuation (i.e. de-challenge / re-challenge
information). An assessment of causality of a suspected association should also consider, the presence
of potential alternative causes including other concomitant medications, the underlying disease, the
reporter’s evaluation of causality and the plausibility of a biological and pharmacological relationship.
IX.B.3.2.2. Statistical analyses
Signal detection is now increasingly based on a regular periodic monitoring of large databases of
spontaneous reports of ADRs. Such databases allow generation of statistical reports presenting
information on adverse reactions received over a defined time period for defined active substances or
medicinal products. Various methods have been developed to identify statistics of disproportionate
reporting, i.e. higher reporting than expected for an suspected adverse reaction for an active
substance/medicinal product of interest compared to all other active substances/medicinal products in
the database, (expressed e.g. as a lower bound of the proportionate reporting ratio >1). Given the
limitations of these methods, statistics of disproportionate reporting alone do not necessarily indicate
that there is a signal to be further investigated or that a causal association is present.
Use of statistical tools may not be appropriate in all situations. The size of the data set, the
completeness of the available information and the severity of the adverse reaction(s) should be taken
into account when considering the use of statistical methods and the selection of criteria for the
detection of signals.
The periodicity at which statistical reports should be generated and reviewed may vary according to
the active substance/medicinal product, its indication and any known potential or identified risks. Some
active substances/medicinal products may also be subject to an increased frequency of data
monitoring (see IX.C.2.). The duration for this increased frequency of monitoring may also vary and be
flexible with the accumulation of knowledge of the risk profile associated with the use of the concerned
active substance/medicinal product.
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IX.B.3.2.3. Combination of statistical methods and review of individual case safety reports
Statistical reports may be designed to provide tools for identifying suspected adverse reactions that
meet pre-defined criteria of frequency, severity, clinical importance, novelty or statistical association.
Such filtering tools may facilitate the selection of ICSRs to be reviewed as a first step. The thresholds
used in this filtering process (for example, at least 3 cases reported) may vary according to the extent
of usage of medicinal products and thus the potential public health impact.
Irrespective of the statistical method used, where statistical reports are used to automate the
screening of a database, signal detection should always involve clinical judgement and the
corresponding ICSRs should be individually reviewed, considering their clinical relevance (IX.B.3.2.1.).
The statistical method should therefore be a supporting tool in the whole process of signal detection
and subsequent validation.
IX.B.3.3. Signal validation
Signal validation is the process of evaluating the data supporting the detected signal in order to verify
that the available documentation contains sufficient evidence demonstrating the existence of a new
potentially causal association or a new aspect of a known association, and therefore justifies further
analysis [IR Art 21(1)].
To validate a signal the following should be taken into account:
• Clinical relevance including, for example:
− strength of evidence for a causal effect (e.g. number of reports, exposure, temporal
association, plausible mechanism, de/re-challenge, alternative explanation/confounders);
− seriousness and severity of the reaction and its outcome;
− novelty of the reaction (e.g. new and serious adverse reactions);
− drug-drug interactions;
− reactions occurring in special populations.
• Previous awareness:
− the extent to which information is already included in the summary of product characteristics
(SmPC) or patient leaflet;
− whether the association has already been assessed in a PSUR or RMP, or was discussed at the
level of a scientific committee or has been subject to a regulatory procedure.
In principle only a new signal for which there is no previous awareness should be validated. However,
an already known association may give rise to a new signal if its apparent frequency of reporting, its
duration, its severity or a change in the previously reported outcome (such as new fatality) suggests
new information as compared with the information included in the SmPC or previously assessed by the
competent authority.
• Availability of other relevant sources of information providing a richer set of data on the same
association:
− literature findings regarding similar cases;
− experimental findings or biological mechanisms;
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− screening of databases with larger datasets (e.g. EudraVigilance when the signal was sourced
initially by data from national or company-specific database).
The magnitude and clinical significance of a signal may also be examined by descriptive analyses in
other available data sources or by analysis of the characteristics of exposed patients and their
medicinal product utilisation patterns.
Signals for which the validity is not confirmed may deserve special attention in subsequent analyses
i.e. it may be appropriate to continue to monitor the potential signal until there is enough evidence to
confirm the signal. For example, there might be an inadequate case documentation or a supporting
evidence of a causal association only in some of the ICSRs. In such scenarios, new cases of the same
adverse reaction or follow-up reports of previously received cases should be reviewed at appropriate
time intervals to ensure that all relevant cases are considered.
Marketing authorisation holders and competent authorities should establish tracking systems to
capture the outcome of the validation of signals including the reasons why signals were not validated
as well as information that would facilitate further retrieval of ICSRs and validation of signals.
IX.B.3.4. Signal analysis and prioritisation
A key element of the signal management process is to promptly identify validated signals with
important public health impact or that may significantly affect the benefit-risk profile of the medicinal
product in treated patients. These signals require urgent attention and need to be prioritised for further
management without delay. This prioritisation process should consider:
• the impact on patients depending on the severity, reversibility, potential for prevention and clinical
outcome of the association;
• the consequences of treatment discontinuation on the disease and the availability other therapeutic
options;
• the strength and consistency of the evidence supporting an association, e.g., biological plausibility,
a high number of cases reported in a short period of time, the measure of disproportionality of
reporting and rapid increase of that measure over time and identification of the signal in different
settings (e.g. general practice and hospital settings), data sources or countries;
• clinical context (e.g. whether the association suggest a clinical syndrome that may include other
reactions);
• the public health impact, including the extent of utilisation of the product in the general population
and in special populations (e.g. pregnant women, children or the elderly) and the patterns of
medicinal product utilisation (e.g. off-label use or misuse). The public health impact may include an
estimation of the number of patients that may be affected by an adverse reaction and this number
could be considered in relation to the size of the general population, the population with the target
disease and the treated population;
• increased frequency or severity of a known adverse reaction;
• novelty of the suspected adverse reaction, e.g. when an unknown suspected adverse reaction
occurs shortly after the marketing of a new medicinal product;
• if a marketing authorisation application for a new active substance is still under evaluation.
In some circumstances, priority can also be given to signals identified for medicinal products or events
with potential high media and pharmacovigilance stakeholder interest in order to communicate the
result to the public and healthcare professionals as early as possible.
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The outcome of signal prioritisation should include a recommendation of the time frame for the
management of the signal.
The outcome of the signal prioritisation process should be entered in the tracking system, with the
justification for the priority attributed.
IX.B.3.5. Signal assessment
The objective of signal assessment is to further evaluate a validated signal so as to identify the need
for additional data collection or for any regulatory action. It consists of an assessment of the available
pharmacological, non-clinical and clinical data and information from other sources. This review should
be as complete as possible regarding the sources of information, including the application dossier,
literature articles, spontaneous reports, expert consultation, and information held by marketing
authorisation holders and competent authorities. When information is drawn from a range of sources,
the strengths and limitations of each source should be considered in order to assess the contribution
they can provide to the overall evaluation of the signal in terms of a recommendation for action.
Summarising information from different data sources also requires the choice of an internationally
agreed case definition (e.g. Brighton collaboration case definition for vaccines). If no such definition
exists, an operational definition should be developed.
Signals may need to be assessed at a broader level e.g. at the therapeutic or system organ class level
or at the level of a Standardised MedDRA1 Query (i.e. SMQ). The search for information to assess the
significance of a signal may also need to be extended to other products of the class and to other
adverse reactions, such as to other terms linked to a complex disease (e.g. optic neuritis as a possible
early sign of multiple sclerosis), to a prior stage of a reaction (e.g. QT prolongation and torsades de
pointes) or to clinical complications of the adverse reaction of interest (e.g. dehydration and acute
renal failure).
Gathering information from various sources may take time. For a new signal of a serious or severe
adverse reaction, measures should be taken at any stage in the management of a signal including
detection, if the information already available supports the conclusion that there is a potential risk that
needs to be prevented or minimised in a timely manner.
IX.B.3.6. Recommendation for action
Signal assessment results in a recommendation that either no further action is required at this point in
time or a further action is needed. Although the recommendation for action normally takes place in a
logical sequence after signal assessment based on the extent of the information, the need for action
should be considered throughout the signal management process. For example, the first case of an
adverse reaction indicating a manufacturing defect may require immediate recall of a product batch.
The review of available information at the signal validation or signal prioritisation stages may similarly
conclude that the evidence is sufficiently strong to introduce temporary measures. In such situations, it
is still necessary to proceed with a formal assessment of the signal to confirm or not the safety issue in
order to extend or lift the temporary measures.
The recommendation for action may include a request for:
• immediate measures including the possibility of suspending the marketing authorisation of the
medicinal product;
1 MedDRA® the Medical Dictionary for Regulatory Activities terminology is the international medical terminology developed
under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH)
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• additional information to be provided by the marketing authorisation holder, e.g. in order to
confirm if a conclusion is valid for all indications and patient groups;
• periodic review of the signal, for example through PSURs (see Module VII);
• additional investigations or risk minimisation activities;
• an update of the product information through a regulatory procedure;
• conduct of a post-authorisation safety study (see Module VIII).
Whenever actions are requested of a marketing authorisation holder, the request should specify a
timeframe by which they should be completed, including provision of progress reports and interim
results, proportionate to the severity and public health impact of the signal.
IX.B.3.7. Exchange of information
Information on validated signals, Emerging Safety Issues and the outcome of signal assessments
should be exchanged between competent authorities and marketing authorisation holders.
Marketing authorisation holders should communicate signals that may have implications for public
health and the benefit-risk profile of a product immediately to the competent authorities as an
Emerging Safety Issue (see Module VI), and when appropriate this should include proposals for action.
The outcomes of signal assessment involving new or changed risks and risks that have an impact on
the benefit-risk balance of the concerned active substance/medicinal products should be communicated
to the public including health care professionals and patients (see IX.C.6.) as well as to the concerned
marketing authorisation holders.
IX.B.4. Quality requirements
IX.B.4.1. Tracking
All validation, prioritisation, assessment, timelines, decisions, actions, plans, reporting as well as all
other key steps should be recorded and tracked systematically. Tracking systems should be used for
documentation and should also include signals, for which the validation process conducted was not
suggestive of a new potentially causal association, or a new aspect of a known association. All records
need to be archived [IR Art 24(1)] (see Module I).
IX.B.4.2. Quality systems and documentation
An essential feature of a signal management system is that it is clearly documented to ensure that the
system functions properly and effectively, that the roles, responsibilities and required tasks are
standardised, that these tasks are conducted by people with appropriate expertise and are clear to all
parties involved and that there is provision for appropriate control and, when needed, improvement of
the system. Therefore, a system of quality assurance and quality control consistent with the quality
system standards should be in place and applied to all signal management processes (see Module I).
Detailed procedures for this quality system should be developed, documented and implemented. The
organisational roles and responsibilities for the activities and maintenance of documentation, quality
control and review, and for ensuring corrective and preventive action need to be assigned and
recorded. This should include the responsibilities for quality assurance auditing of the signal
management system, including auditing of sub-contractors. Data and document confidentiality (per the
applicable regulations), security and validity (including integrity when transferred) should be
guaranteed.
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Through their tracking system, all parties should keep an audit trail of their signal management
activities and of the relevant queries and their outcomes, including how signals have been detected,
validated, confirmed and assessed [IR Art 24(2)].
Documentation may be requested from the marketing authorisation holders demonstrating compliance
with these provisions and reviewed before and after marketing authorisation.
Staff should be specifically trained in signal management activities in accordance with their roles and
responsibilities. The training system and location of the training records should be documented, and
curricula vitae and job descriptions should be archived.
IX.C. Operation of the EU network
IX.C.1. Roles and responsibilities
Within the context of the operation of the EU regulatory network, the marketing authorisation holders,
the Agency and national competent authorities should continuously monitor the data available in the
EudraVigilance database to determine whether there are new risks or whether risks have changed and
whether those risks have an impact on the benefit-risk balance. A recognised signal detection
methodology should be applied and detected signals should be validated, as appropriate.
The Agency and national competent authorities shall cooperate in the monitoring of the data available
in the EudraVigilance database [IR Art 18(1)].
Regarding medicinal products authorised in accordance with Regulation (EC) No 726/2004 (centrally
authorised products (CAPs)) the Agency shall be assisted in the monitoring of data in EudraVigilance
by the rapporteur appointed by the PRAC in accordance with Article 62(1) of that Regulation [IR Art
22(5)].
For medicinal products authorised in accordance with Directive 2001/83/EC in more than one Member
State and for active substances contained in several medicinal products where at least one marketing
authorisation has been granted in accordance with Directive 2001/83/EC, Member States may agree
within the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh),
in collaboration with the PRAC, to appoint a lead Member State for the monitoring of data in the
EudraVigilance database and for validation and confirmation of signals on behalf of the other Member
States. The lead Member State may be supported by a co-leader, which shall assist the lead Member
State in the fulfilment of its tasks. Any such appointment shall be reviewed at least every four years
[IR Art 22(1)]. When appointing a lead Member State, and as appropriate a co-leader, the CMDh in
collaboration with the PRAC, may take into account whether any Member State is acting as reference
Member State, in accordance with Article 28(1) of Directive 2001/83/EC, or as a rapporteur for the
assessment of periodic safety update reports in accordance with Article 107(e) of that Directive [IR Art
22(2)].
All Member States shall remain responsible for monitoring the data in the EudraVigilance database in
accordance with Article 107h(1)(c) and Article 107h(3) of Directive 2001/83/EC [IR Art 22(4)].
The national competent authorities and the Agency shall validate and confirm any signal that has been
detected by them in the course of their continuous monitoring of the data in EudraVigilance database
[IR Art 21(4)].
For medicinal products or active substances where a rapporteur has been appointed by the PRAC, this
rapporteur should confirm validated signals. For medicinal products or active substances where a lead
Member State has been appointed, this lead Member State should confirm validated signals.
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Confirmation by the PRAC rapporteur or the lead Member State means communication through the
European Pharmacovigilance Issues Tracking Tool (EPITT) (see IX.C.5.) that the signal is valid. A
justification should be provided when the signal is not confirmed. All confirmed signals shall be
transmitted to the PRAC. For such medicinal products or active substances for which a lead Member
State has been appointed, the lead Member State should validate and confirm as a single step the
signals it has detected. For such medicinal products or active substances where a lead Member State
has not been appointed, the national competent authority should validate and confirm as a single step
the signals it has detected.
IX.C.1.1. Roles and responsibilities of the Agency
The Agency:
• shall make public on the European medicines web-portal a list of active substances/medicinal
products and the authority (lead Member State, co-lead Member State or the Agency) responsible
for their monitoring in EudraVigilance [IR Art 22(3)];
• following consultation with the PRAC may publish a list of medical events that have to be taken into
account for the detection of a signal [IR Art 19(2)];
• shall support the monitoring of the data in the EudraVigilance database by providing national
competent authorities with access to:
− data outputs and statistical reports allowing a review of all adverse reactions reported to
EudraVigilance in relation with an active substance or a medicinal product;
− customised queries supporting the evaluation of individual case safety reports and case series;
− customised grouping and stratification of data enabling the identification of patient groups with
a higher risk of occurrence of adverse reactions or with a risk of a more severe adverse
reaction;
− statistical signal detection methods [IR Art 23];
• shall ensure appropriate support for the monitoring of the data in EudraVigilance by marketing
authorisation holders [IR Art 23];
• should prepare a technical document establishing common requirements for signal detection and
describing EudraVigilance data outputs and statistical reports;
• shall administer the European Pharmacovigilance Issues Tracking Tool (EPITT) for validated signals
that require further assessment [IR Art 21(5)];
• shall take the lead for EudraVigilance data monitoring, signal detection and signal validation for
CAPs and for active substances contained in several medicinal products, where at least one
marketing authorisation has been granted in accordance with Regulation (EC) 726/2004;
• shall enter validated signals it has detected into EPITT;
• should validate (including, if appropriate, in the EudraVigilance database) and enter into EPITT any
other signal communicated by a third party (e.g. regulatory authority from outside the EU),
involving a CAP or an active substance for which the EudraVigilance data monitoring is performed
by the Agency;
• shall confirm in collaboration with the Member States as soon as possible and no later than 30 days
from its receipt any validated signal communicated by marketing authorisation holders involving a
CAP or an active substance for which the EudraVigilance data monitoring is performed by the
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Agency. In this context, where the validity of the signal is not confirmed, special attention shall be
paid to any follow-up information which may allow for the signal’s confirmation [IR Art 21(3)], see
IX.B.3.3;
• shall transmit confirmed signals to the PRAC for initial analysis and prioritisation in accordance with
Article 28a(2) of Regulation (EC) No 726/2004 [IR Art 21(5)];
• shall forthwith inform the concerned marketing authorisation holder(s) of the conclusions of the
PRAC of the assessment of any confirmed signal [IR Art 21(6)];
• shall keep an audit trail of its signal detection activities [IR Art 24(1)].
IX.C.1.2. Roles and responsibilities of the lead Member State
The lead Member State:
• shall take the lead for EudraVigilance data monitoring, signal detection, signal validation and signal
confirmation for active substances/medicinal products for which it has been appointed the lead;
• shall confirm signals that have been detected and validated by a national competent authority for
these substances/medicinal products;
• shall enter into EPITT signals it has detected, validated and confirmed itself for these
substances/medicinal products
• should validate (including, if appropriate, in the EudraVigilance database) and enter into EPITT any
other signal communicated by a third party (e.g. regulatory authority from outside the EU) for
these substances/medicinal products;
• shall confirm as soon as possible and no later than 30 days from its receipt any validated signal
communicated by marketing authorisation holders for these substances/medicinal products. In this
context, where the validity of the signal is not confirmed, special attention shall be paid to any
follow-up information which may allow for the signal’s confirmation [IR Art 21(3)], see IX.B.3.3.;
• shall keep an audit trail of their signal detection activities [IR Art 24 (1)].
IX.C.1.3. Roles and responsibilities of the national competent authorities
The national competent authorities shall specifically monitor data originated in their territory [IR Art
18(4)], including data arising from sources mentioned in IX.B.1.
If a lead Member State or the Agency has been appointed for the monitoring of an active
substance/medicinal product, the national competent authorities:
− should enter validated signals it has detected into EPITT for the lead Member State or the
rapporteur appointed by the PRAC to confirm.
If no lead Member State or the Agency has been appointed for the monitoring of an active
substance/medicinal product, the national competent authorities:
− shall monitor the data of the EudraVigilance database for substances/medicinal products
authorised in their territory;
− shall validate and confirm any signal they have detected from EudraVigilance for
substances/medicinal products authorised in their territory;
− shall enter validated and confirmed signal they have detected into EPITT for
substances/medicinal products authorised in their territory;
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− shall confirm as soon as possible and no later than 30 days from its receipt any validated signal
communicated by a marketing authorisation holder for an active substance/medicinal product
authorised in their territory. In this context, where the validity of the signal is not confirmed,
special attention shall be paid to any follow-up information which may allow for the signal’s
confirmation [IR Art 21(3)], see IX.B.3.3.
The national competent authorities shall keep an audit trail of their signal detection activities [IR Art 24
(1)].
IX.C.1.4. Roles and responsibilities of the Pharmacovigilance Risk
Assessment Committee
The Pharmacovigilance Risk Assessment Committee (PRAC):
• shall prioritise validated and confirmed signals for further assessment [REG Art 28a];
• should nominate a rapporteur for the assessment of the validated and confirmed signals with a
time frame for the assessment;
• shall transmit to the CHMP or to the CMDh, as appropriate, any recommendations for action
following the signal assessment;
• shall perform a regular review of the signal management methodology to be used and publish
recommendations as appropriate [IR Art 20 (3)];
• should review at least every four years the lead and the co-lead Member States responsible for the
monitoring of the data in EudraVigilance [IR Art 22(1)];
• should review the list of medical events that have to be taken into account for the detection of a
signal before their publication by the Agency [IR Art 19(2)].
IX.C.1.5. Roles and responsibilities of marketing authorisation holder
The marketing authorisation holder should continuously monitor the safety of its medicinal products
and inform the authorities of any changes that might have an impact on the marketing authorisation.
The marketing authorisation holder:
• shall monitor the data in EudraVigilance to the extent of their accessibility [IR Art 18(2)]. See also
EudraVigilance access rights for stakeholder group III in the EudraVigilance Access Policy for
Medicines for Human Use2. The frequency of the monitoring should be at least once monthly and
shall be proportionate to the identified risk, the potential risk and the need for additional
information [IM Art 18(3)];
• shall validate any signal detected from EudraVigilance and shall forthwith inform the responsible
competent authority for signal detection in line with the list as published by the Agency [IR Art
21(2)]. For the validation step, the elements of information presented in IX.B.3.3. should be taken
into account;
• should notify in writing as an Emerging Safety Issue to the competent authorities in Member States
where the medicinal product is authorised and to the Agency via email (P-PV-emerging-safety-
issue@ema.europa.eu) (see also Module VI), any safety issue arising from its signal detection
2 EudraVigilance access policy for medicines for human use published on 23 August 2011
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2011/07/WC500108538.pdf
mailto:P-PV-emerging-safety-issue@ema.europa.eu
mailto:P-PV-emerging-safety-issue@ema.europa.eu
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2011/07/WC500108538.pdf
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activity which could have a significant impact on the benefit-risk balance for a medicinal product
and/or have implications for public health;
• should collaborate with the PRAC for the assessment of the signals by providing additional
information upon request;
• should keep an audit trail of its signal detection activities.
IX.C.2. Periodicity of data monitoring in EudraVigilance
National competent authorities and the Agency shall ensure the continuous monitoring of data in the
EudraVigilance database with a frequency proportionate to the identified risk, the potential risk and the
need for additional information [IR Art 18(3)]. The monitoring should be based on a periodic review of
statistical outputs (e.g. reaction monitoring reports) to determine whether there are new or changed
risks in the safety profile of an active substance/medicinal product. The statistical outputs should
contain ADRs in a structured hierarchy (e.g. MedDRA hierarchy) by active substance(s)/medicinal
product(s) and allow filters and thresholds to be applied on several fields as appropriate.
The baseline frequency for reviewing the statistical outputs from EudraVigilance should be once-
monthly. An increase to the baseline frequency of data monitoring in EudraVigilance may be decided
by the lead Member State, the national competent authority or the Agency if justified by the identified
or potential risks of the product or by the need for additional information. The PRAC should be
informed of the decision and the justification.
For products subject to additional monitoring (see Module X), the frequency for reviewing the
statistical outputs should be every 2 weeks until the end of additional monitoring. A 2-week frequency
for reviewing the statistical outputs may also be applied for any other product taking into account the
following criteria:
• any product considered to have an identified or potential risk that could impact significantly on the
benefit-risk balance or have implications for public health. This may include risks associated with
significant misuse, abuse or off-label use. The product may be moved back to baseline frequency
of monitoring if risks are not confirmed;
• any product for which the safety information is limited due to low patient exposure during drug
development, including products authorised under conditional approval or under exceptional
circumstances, or for which there are vulnerable or poorly studied patient populations or important
missing information (e.g. children, pregnant women, renal-impaired patients) while post-marketing
exposure is likely to be significant;
• any product that contains active substances already authorised in the EU but is indicated for use in
a new patient population or with a new route of administration;
• any product for which the existing marketing authorisation has been significantly varied (e.g.
changes to indication, posology, pharmaceutical form or route of administration), thereby
modifying the exposed patient population or the safety profile.
Confirmation of a signal arising from the EudraVigilance data monitoring activities does not necessarily
imply that the product has to be more frequently monitored and a risk proportionate approach should
be applied.
More frequent monitoring than every 2 weeks should be based on a proposal from the lead Member
State, national competent authority or the Agency. It should be targeted to a safety concern of interest
especially during public health emergencies (e.g. pandemics) and may be applied in the context of
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customised queries or near real-time alerts3 conducted in the EudraVigilance Data Analysis System
(EVDAS).
IX.C.3. Signal analysis, prioritisation and assessment by the
Pharmacovigilance Risk Assessment Committee (PRAC)
When the Agency or national competent authority validating or confirming a signal considers urgent
action is required before the next PRAC meeting it should trigger the Rapid Alert procedure (see
Module XII). All other signals that have been detected, validated and confirmed by the Agency or a
national competent authority should be sent to the PRAC for consideration at its next meeting. In its
consideration of a signal, the PRAC should agree on a prioritisation based on the individual patient and
public health impact of the potential change to the benefit-risk balance. Depending on the
prioritisation, an analysis of the need for further assessment or for any immediate recommendation for
action should be made, taking into account the time frame proposed by the Agency or the national
competent authority that detected the signal.
When PRAC considers a signal as a high priority at a given meeting, a recommendation on the
action(s) required should be made during the same meeting and appropriate procedure(s) should be
initiated by the Agency and/or national competent authorities in conjunction with the marketing
authorisation holder
When it considers that further signal assessment is needed, the PRAC should nominate a rapporteur
and should define a timeframe for this assessment taking into account the prioritisation of the signal.
The rapporteur for the signal assessment should transmit to the PRAC an assessment stating whether
there may be new risks, whether risks have changed or whether there is a change in the benefit-risk
balance in relation to the concerned active substance or medicinal product. The assessment should also
include a proposed recommendation for action(s), if appropriate. The PRAC can also conclude that no
action is required at EU level at this time point.
Following review of the rapporteur's assessment report, the PRAC should make a recommendation for
action(s), stating the reasons on which it is based. The recommendation should include an
implementation timetable for completion of any actions requested of the marketing authorisation
holder commensurate with the extent and seriousness of the matter in accordance with Article 107h(2)
of Directive 2001/83/EC and Article 28a(2) of Regulation (EC) 726/2004.
IX.C.4. Processes for EU regulatory follow-up
The recommendation for action of the PRAC should be sent to the CHMP in the case of an active
substance that is centrally authorised and to the CMDh in the case of an active substance that is
nationally authorised including authorisation through the mutual recognition or decentralised
procedure.
The CHMP or CMDh may decide on any or a combination of the following actions:
• the marketing authorisation holder should conduct further evaluation of data and provide the
results of that evaluation according to a defined timeline;
• the marketing authorisation holder should submit an ad-hoc PSUR;
• the marketing authorisation holder should sponsor a post-authorisation study according to an
agreed protocol and submit the final results of that study;
3 EVDAS automated data processing and network transmission takes usually 1 day
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• the marketing authorisation holder should be requested to submit a RMP or an updated RMP;
• the marketing authorisation holder should take any measures that are required for ensuring the
safe and effective use of the medicinal product;
• the marketing authorisation should be varied, suspended, revoked or not renewed;
• the Member States or the Commission should initiate as appropriate, the procedure provided for in
Article 31 or in Section 4, Urgent Union Procedure or in Article 31 where appropriate, of Directive
2001/83/EC;
• urgent safety restrictions should be imposed in accordance with Article 22 of Regulation (EC)
1234/2008;
• an inspection should take place in order to verify that the marketing authorisation holder for the
medicinal product satisfies the pharmacovigilance requirements laid down in Titles IX and XI of
Directive 2001/83/EC;
• the medicinal product should be included in the list of medicinal products that are subject to
additional monitoring within the scope defined in Article 23 of Regulation (EC) 726/2004.
Where recommended by the PRAC and agreed by the CHMP or the CMDh as appropriate, a procedure
should be initiated with a timetable in which the marketing authorisation should be varied, suspended,
revoked or not renewed where applicable.
IX.C.5. Record management in the EU regulatory network
The Agency and the national competent authorities shall keep an audit trail of all their signal
management activities relating to EudraVigilance and of the relevant queries and their outcomes.
Any signal that has been detected and validated by the Agency or a national competent authority in
line with the processes described in section IX.B. should be entered into the web-based European
Pharmacovigilance Issues Tracking Tool (EPITT) administered by the Agency. All subsequent
evaluations, timelines, decisions, actions, plans, reporting and all other key steps should be recorded
and tracked systematically in EPITT by the Agency or the national competent authority in line with the
guidance document Exchange of Information Relating to Signals through EPITT by the EU Regulatory
Network (EMA/383041/2011).
IX.C.6. Transparency
Article 26(1) of Regulation (EC) 726/2004 states that the Agency shall, in collaboration with the
Member States and the Commission, set up and maintain a European medicines web-portal for the
dissemination of information on medicinal products authorised in the EU. This information will include
the conclusions of the PRAC following the assessment of signals and any recommendations.
IX.A. Introduction
IX.B. Structures and processes
IX.B.1. Sources of data and information
IX.B.2. Methodology for signal detection
IX.B.3. The signal management process
IX.B.3.1. Introduction
IX.B.3.2. Signal detection
IX.B.3.2.1. Review of individual case safety reports
IX.B.3.2.2. Statistical analyses
IX.B.3.2.3. Combination of statistical methods and review of individual case safety reports
IX.B.3.3. Signal validation
IX.B.3.4. Signal analysis and prioritisation
IX.B.3.5. Signal assessment
IX.B.3.6. Recommendation for action
IX.B.3.7. Exchange of information
IX.B.4. Quality requirements
IX.B.4.1. Tracking
IX.B.4.2. Quality systems and documentation
IX.C. Operation of the EU network
IX.C.1. Roles and responsibilities
IX.C.1.1. Roles and responsibilities of the Agency
IX.C.1.2. Roles and responsibilities of the lead Member State
IX.C.1.3. Roles and responsibilities of the national competent authorities
IX.C.1.4. Roles and responsibilities of the Pharmacovigilance Risk Assessment Committee
IX.C.1.5. Roles and responsibilities of marketing authorisation holder
IX.C.2. Periodicity of data monitoring in EudraVigilance
IX.C.3. Signal analysis, prioritisation and assessment by the Pharmacovigilance Risk Assessment Committee (PRAC)
IX.C.4. Processes for EU regulatory follow-up
IX.C.5. Record management in the EU regulatory network
IX.C.6. Transparency
29.07.2014
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See websites for contact details
European Medicines Agency www.ema.europa.eu
Heads of Medicines Agencies www.hma.eu
The European Medicines Agency is
an agency of the European Union
© European Medicines Agency and Heads of Medicines Agencies, 2013.
Reproduction is authorised provided the source is acknowledged.
19 April 2013
EMA/169546/2012
Guideline on good pharmacovigilance practices (GVP)
Module X – Additional monitoring
Draft finalised by the Agency in collaboration with Member States 25 May 2012
Draft agreed by ERMS FG 30 May 2012
Draft adopted by Executive Director 22 June 2012
Released for public consultation 27 June 2012
End of consultation (deadline for comments) 24 August 2012
Revised draft finalised by the Agency in collaboration with Member
States
21 March 2013
Revised draft agreed by ERMS FG 27 March 2013
Revised draft adopted by Executive Director as final 19 April 2013
Date for coming into effect 25 April 2013
Guideline on good pharmacovigilance practices (GVP) – Module X
EMA/169546/2012 Page 2/9
Table of contents
X.A. Introduction ......................................................................................... 3
X.B. Structures and processes ..................................................................... 4
X.B.1. Principles for assigning additional monitoring status to a medicinal product .............. 4
X.B.2. Communication and transparency........................................................................ 4
X.C. Operation of the EU network ................................................................ 5
X.C.1. Criteria for including a medicinal product in the additional monitoring list ................. 5
X.C.1.1. Mandatory scope ............................................................................................ 5
X.C.1.2. Optional scope ............................................................................................... 5
X.C.2. Criteria for defining the initial time period of maintenance in the additional monitoring
list ............................................................................................................................ 6
X.C.2.1. Mandatory scope ............................................................................................ 6
X.C.2.2. Optional scope ............................................................................................... 6
X.C.3. Roles and responsibilities ................................................................................... 6
X.C.3.1. The European Commission ............................................................................... 6
X.C.3.2. The Agency .................................................................................................... 6
X.C.3.3. National competent authorities ......................................................................... 7
X.C.3.4. The Pharmacovigilance Risk Assessment Committee (PRAC) ................................ 7
X.C.3.5. The Marketing authorisation holder ................................................................... 7
X.C.4. Creation and maintenance of the list .................................................................... 8
X.C.4.1. Process for the creation of the list ..................................................................... 8
X.C.4.2. Process for the maintenance of the list .............................................................. 8
X.C.4.2.1. Inclusion of medicinal products in the list........................................................ 8
X.C.5. Black symbol and explanatory statements ............................................................ 9
X.C.6. Transparency .................................................................................................... 9
Guideline on good pharmacovigilance practices (GVP) – Module X
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X.A. Introduction
Pharmacovigilance is a vital public health function with the aim of rapidly detecting and responding to
potential safety hazards associated with the use of medicinal products.
A medicinal product is authorised on the basis that, its benefit-risk balance is considered to be positive
at that time for a specified target population within its approved indication (s). However, not all risks
can be identified at the time of initial authorisation and some of the risks associated with the use of a
medicinal product emerge or are further characterised in the post-authorisation phase of the product’s
lifecycle. . To strengthen the safety monitoring of medicinal products, the 2010 EU Pharmacovigilance
legislation, further amended in 2012, has introduced a framework for enhanced risk proportionate
post-authorisation data collection for medicinal products, including the concept of additional monitoring
for certain medicinal products.
As defined in Article 23 of Regulation (EC) No 726/2004 (REG) and Article 11 of Directive 2001/83/EC
(DIR), the Agency shall, in collaboration with the Member States, set up, maintain and make public a
list of medicinal products that are subject to additional monitoring (hereafter referred to as “the list”).
These medicinal products will be readily identifiable by an inverted equilateral black triangle as
stipulated in the Implementing Regulation (EU) No 198/2013. That triangle will be followed by an
explanatory statement in the summary of product characteristics (SmPC) as follows:
“This medicinal product is subject to additional monitoring. This will allow quick identification of new
safety information. Healthcare professionals are asked to report any suspected adverse reactions. See
section 4.8 for how to report adverse reactions.”
A similar statement will also be included in the package leaflet. This explanatory statement should
encourage healthcare professionals and patients to report all suspected adverse reactions.
The pharmacovigilance provisions of Regulation (EC) No 726/2004 and of Directive 2001/83/EC have
been recently amended by Regulation (EU) No 1027/2012 and Directive 2012/26/EU respectively.
These amendments have impacted on the content and the scope of Article 23 of the REG and will be
applicable for centrally authorised products on 5 June 2013. This GVP takes into account the new
provisions relating to the list of products which require additional monitoring.
Post-authorisation spontaneous Adverse Drug Reactions (ADR) reports remain a cornerstone of
pharmacovigilance. Data from ADR reports is a key source of information for signal detection activities
(see Module IX). Increasing the awareness of healthcare professionals and patients of the need to
report suspected adverse drug reactions and encouraging their reporting is therefore an important
means of monitoring the safety profile of a medicinal product.
The concept of additional monitoring originates primarily from the need to enhance the ADR reporting
rates for newly authorised products for which the safety profile might not be fully characterised or for
products with newly emerging safety concerns that also need to be better characterised. The main
goals are to collect additional information as early as possible to further elucidate the risk profile of
products when used in clinical practice and thereby informing the safe and effective use of medicinal
products.
This Module is divided in two sections:
X.B. provides general principles for assigning additional monitoring status to medicinal products
and on communication and transparency aspects.
X.C. describes the operation of the EU network regarding the supervision of additional monitoring
status, the communication strategy and the impact on pharmacovigilance activities.
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X.B. Structures and processes
X.B.1. Principles for assigning additional monitoring status to a medicinal
product
All medicines are authorised on the basis that the benefit of treatment is considered to outweigh the
potential risks. To come to this conclusion for a marketing authorisation, data from clinical trials
conducted during the development of a medicine are assessed. However, adverse reactions which
occur rarely or after a long time may become apparent only once the product is used in a wider
population and/or after long term use. In addition, the benefits and risks of a medicine may have been
evaluated in conditions which may differ from those in everyday medical practice, e.g. clinical trials
might exclude certain types of patients with multiple co-morbidities or concomitant medications.
Therefore, after a medicine is placed on the market, its use in the wider population requires continuous
monitoring. Marketing authorisation holders and competent authorities continuously monitor
medicinal products for any information that becomes available and assess whether it impacts on the
benefit-risk profile of the medicinal product. However, for certain medicinal products enhanced post-
authorisation data collection is needed to ensure that any new safety hazards are identified as
promptly as possible and that appropriate action can be initiated immediately. Therefore, in order to
strengthen the monitoring of certain medicinal products and in particular to encourage the
spontaneous reporting of ADRs, the concept of additional monitoring has been introduced.
Additional monitoring status can be assigned to a medicinal product at the time of granting a
marketing authorisation or in some cases at later stages of the product life cycle for a medicinal
product for which a new safety concern has been identified. The additional monitoring status is
particularly important when granting marketing authorisation for medicinal products containing a new
active substance and for all biological medicinal products, which are priorities for pharmacovigilance.
Competent authorities may also require additional monitoring status for a medicinal product which is
subject to specific obligations e.g. the conduct of a Post-Authorisation Safety Study (PASS) or
restrictions with regards to the safe and effective use of the medicinal product.
X.B.2. Communication and transparency
The additional monitoring status needs to be communicated to healthcare professionals and patients in
such a way that it increases reporting of suspected adverse reactions without creating undue alarm.
This can be achieved for example by highlighting the need to better characterise the safety profile of a
new medicinal product by identifying additional risks but placing those potential risks in the context of
the known benefits for this product. A publicly available list of medicinal products with additional
monitoring status should be kept up to date by the Agency In addition, healthcare professionals and
patients should be enabled to easily identify those products through their product labelling. The
publication of the list together with appropriate communication should encourage healthcare
professionals and patients to report all suspected adverse drug reactions for all medicinal products
subject to additional monitoring.
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X.C. Operation of the EU network
X.C.1. Criteria for including a medicinal product in the additional monitoring
list
X.C.1.1. Mandatory scope
According to Article 23(1) of Regulation (EC) No 726/2004 (REG), it is mandatory to include the
following categories of medicinal products in the list:
medicinal products authorised in the EU that contain a new active substance which, on 1 January
2011, was not contained in any medicinal product authorised in the EU;
any biological medicinal product not covered by the previous category and authorised after 1
January 2011;
products for which a PASS was requested at the time of marketing authorisation (point (cb) of
Article 9(4) of Regulation (EC) No 726/2004 and point( b) of Article 21a of Directive 2001/83/EC);
products authorised with specific obligations on the recording or suspected adverse drug reactions
exceeding those referred to in Chapter 3 of Directive 83/2001/EC (point (cb) of Article 9(4) of
Regulation (EC) No 726/2004 and point (c) of Article 21a of Directive 2001/83/EC);
products for which a PASS was requested following the grant of marketing authorisation (Article
10a(1) of Regulation (EC) No 726/2004 and point (a) of Article 22a (1) of Directive 2001/83/EC);
products which were granted a conditional marketing authorisation (Article 14(7) of Regulation
(EC) No 726/2004));
products authorised under exceptional circumstances (Article 14(8) of Regulation (EC) No
726/2004) and Article 22 of Directive 2001/83/EC)).
X.C.1.2. Optional scope
As set out in Article 23(2) of Regulation (EC) No 726/2004 there is the possibility to include in the list
medicinal products subject to conditions, not falling under the mandatory scope. This can be done at
the request of the European Commission or a national competent authority, as appropriate, following
consultation with the Pharmacovigilance Risk Assessment Committee (PRAC).
As reflected in Article 23(2) of Regulation (EC) No 726/2004 the situations that could form the basis
for a request for inclusion in the list are:
When a marketing authorisation is granted subject to one or more of the following:
conditions or restrictions with regard to the safe and effective use of the medicinal product
[REG Art 9(4)(c), DIR Art 21a(d)];
measures for ensuring the safe use of the medicinal product to be included in the risk
management system [REG Art 9(4)(ca), DIR Art 21a(a)];
an obligation to conduct a post-authorisation efficacy study [REG Art 9(4)(cc)DIR Art 21a(f)];
the existence of an adequate pharmacovigilance system [DIR Art 21a(e)].
The scope of Article 23(2) of Regulation (EC) No 726/2004 does not only include medicinal products
which are authorised or for which conditions are established after entry into force of the new
pharmacovigilance legislation but also medicinal products which were authorised or made subject to
Guideline on good pharmacovigilance practices (GVP) – Module X
EMA/169546/2012 Page 6/9
conditions before such date, provided they fall within one or more of the above situations for the
optional scope.
Pharmacovigilance rules in general and additional monitoring specifically take into account that the full
safety profile of medicinal products can only be confirmed after products have been placed on the
market. Due consideration should, therefore, be given to the merit of inclusion of a medicinal product
in the list in terms of increasing awareness about the safe and effective use of a medicinal product
and/or providing any additional information for the evaluation of the product. In this regard, the
decision to include a medicinal product subject to conditions in the list should take account of the
nature and scope of the conditions or obligations placed on the marketing authorisation including their
potential public health impact. The decision should also consider the usefulness of the additional
monitoring status in relation to other additional pharmacovigilance activities proposed in the risk
management plan, for example in relation to the objectives of PASS.
X.C.2. Criteria for defining the initial time period of maintenance in the
additional monitoring list
X.C.2.1. Mandatory scope
For medicinal products containing new active substances as well as for all biological medicinal products
approved after 1 January 2011 the initial period of time for inclusion is five years after the Union
Reference Date (URD) referred to in Article 107c(5) of Directive 2001/83/EC.
X.C.2.2. Optional scope
The period of time for inclusion in the list of medicinal products authorised subject to conditions is
decided by the European Commission or the national competent authority, as appropriate, is linked to
the fulfilment of the conditions and obligations placed on the marketing authorisation.
If new conditions are imposed to the marketing authorisation during a product’s lifecycle, it is
envisaged that a medicinal product previously removed from the list can be added to the list again if
for example the criteria stipulated in Article 23(2) of Regulation (EC) No 726/2004 are met again.
X.C.3. Roles and responsibilities
X.C.3.1. The European Commission
The European Commission decides, based on a recommendation from the PRAC:
if a particular centrally authorised medicinal product subject to conditions as set out in Article
23(2) of Regulation (EC) 726/2004 should be included in the list.
X.C.3.2. The Agency
The Agency:
is responsible for publishing the list of medicinal products that are subject to additional monitoring
on the European web-portal with an electronic link(s) to a webpage where the product information
and the summary of the RMP are publicly available;
will coordinate the gathering of information that should be sent by the competent authorities within
the EU network in order to set up, maintain and publish the list;
is responsible for removing medicinal products from the list after a pre-determined time period;
Guideline on good pharmacovigilance practices (GVP) – Module X
EMA/169546/2012 Page 7/9
will take into account the list of centralised medicinal products subject to additional monitoring in
determining the frequency and processes of its signal detection activities;
will inform the relevant MAH when a centralised medicinal product has been included to the list of
additional monitored products;
will support the process of consultation of the PRAC on the inclusion of medicinal products on the
list.
X.C.3.3. National competent authorities
National competent authorities should:
inform the Agency which nationally authorised medicinal products are to be included in the list and
provide the electronic links to the national webpage where the product information and the
summary of the RMP are publicly available;
decide, based on a recommendation from the PRAC, if a particular nationally authorised medicinal
product subject to conditions as set out in Article 23(2) of Regulation (EC) 726/2004 should be
subject to additional monitoring and therefore included in the list;
make publicly available in their national web-portal the list of medicinal products authorised in their
territory that are subject to additional monitoring. The list shall include an electronic link to a
webpage where the product information and the summary of the RMP are publicly available;
inform the Agency of any update that needs to be made for nationally authorised medicinal
products included in the list that is published by the Agency;
take into account the list of nationally authorised medicinal products subject to additional
monitoring in determining the frequency and processes of their signal detection activities;
inform the relevant MAH when a nationally medicinal product has been included to the list of
additional monitored products.
X.C.3.4. The Pharmacovigilance Risk Assessment Committee (PRAC)
The PRAC:
recommends, upon request of the European Commission or a national competent authority, as
appropriate, if a medicinal product which is subject to conditions as set out in Article 23(2) of
Regulation (EC) 726/2004 should be included in the list.
X.C.3.5. The Marketing authorisation holder
The marketing authorisation holder:
shall include in the SmPC and Package leaflet of their medicinal products subject to additional
monitoring the black triangle symbol and the and the standardised explanatory statement on
additional monitoring;
should include information on the status of additional monitoring in any material to be distributed
to healthcare professionals and patients and should make all efforts to encourage reporting of
adverse reactions, as agreed with national competent authorities;
should provide evidence to the competent authorities concerned on the status of any conditions
imposed by the national competent authorities or the European Commission;
Guideline on good pharmacovigilance practices (GVP) – Module X
EMA/169546/2012 Page 8/9
should submit the relevant variation to include/remove the black symbol, the statement, and the
standardised explanatory sentence from the SmPC and PL, where applicable.
X.C.4. Creation and maintenance of the list
As defined in Article 23 of Regulation (EC) 726/2004 the Agency shall, in collaboration with the
Member States, set up, maintain and make public a list of medicinal products that are subject to
additional monitoring. This list will include the names and active substances of all medicinal products
approved in the EU subject to additional monitoring irrespective of the approval procedure (i.e.
centrally or nationally authorised). In addition, as defined in Article 106 of Directive 2001/83/EC, each
Member State shall make publicly available on their national web-portal the list of medicinal product
authorised in their territory that are subject to additional monitoring, and take all appropriated
measures to encourage patients and health care professional to report any suspected adverse drug
reactions.
X.C.4.1. Process for the creation of the list
The Agency in support of the European Commission will identify the centrally authorised products
requiring additional monitoring. National competent authorities are responsible for identifying the
nationally authorised products requiring additional monitoring.
Only medicinal products that fall under the mandatory scope according to Article 23(1) of Regulation
(EC) 726/2004 will be automatically included in the list. For medicinal products that fall under the
optional scope, consultation with the PRAC is required.
The Agency and the national competent authorities will maintain the information that is publicly
available and ensure that it is up to date. While the Agency will have direct access to relevant data for
centrally authorised products, for nationally authorised products, the Agency will rely on accurate and
timely information provided by national competent authorities with regard to the inclusion or removal
of medicinal products from the list and the provision of the electronic links to the national web-portals
where the product information and the summary of the RMP are publicly available.
The Agency and the Members States will make the list available to the public.
X.C.4.2. Process for the maintenance of the list
The list will be updated monthly following each PRAC meeting, as appropriate.
X.C.4.2.1. Inclusion of medicinal products in the list
Mandatory scope
According to Article 23(1) of Regulation (EC) 726/2004 medicinal product that fall under the
mandatory scope will be automatically included in the list on an ongoing basis In case of medicinal
products approved through the mutual recognition or decentralised procedures, the Reference Member
State (RMS) should inform the Agency once authorisation for such products has been granted. In
addition, each national competent authority included in such procedures should inform the Agency,
within 15 days of granting the marketing authorisation nationally, and provide the electronic links to
their national web-portal where the product information and the summary of the RMP are publicly
available. The Agency will include medicinal products in the list within the next update following receipt
of the European Commission decision, in case of centrally authorised products, or following receipt of
the national competent authorities’ notification.
Guideline on good pharmacovigilance practices (GVP) – Module X
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Optional scope
According to Article 23(2) of Regulation (EC) No 726/2004 medicinal products that fall under the
optional scope, consultation with the PRAC is required prior to inclusion in the list.
In case of mutual recognition or decentralised procedures, the RMS should be the lead and consult the
PRAC as soon as relevant conditions are considered necessary and before the finalisation of the
procedure.
In case of purely national procedures, the national competent authority should consult the PRAC as
soon as relevant conditions are considered necessary and before the finalisation of the procedure.
The Agency will include centrally authorised products in the list within 15 days of receipt of the
European Commission decision. For non-centrally authorised products, once a procedure is finalised
each national competent authority should inform the Agency within 15 days on those particular
medicinal products that are to be included in the list and provide the electronic links to their national
web-portal where the product information and the summary of the RMP are publicly available.
X.C.5. Black symbol and explanatory statements
For medicinal products included in the list, the SmPC shall include the statement:
“This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse
reactions. See section 4.8 for how to report adverse reactions.”,
preceded by an inverted equilateral black triangle (Implementing Regulation (EU) No 198/2013). A
similar statement will also be included in the package leaflet. Once the medicinal product is included or
removed from the list, the marketing authorisation holder shall update the SmPC and the package
leaflet to include or remove, as appropriate, the black symbol, the statement, and the standardised
explanatory statement.
If the decision to include or remove a medicinal product from the list is done during the assessment of
a regulatory procedure (e.g. marketing authorisation application, extension of indication, renewal) the
SmPC and the package leaflet should be updated before finalisation of the procedure in order to
include or remove the black triangle symbol and explanatory statement from the product information.
If the decision to include or remove a medicinal product from the list is done outside a regulatory
procedure, then the marketing authorisation holder is requested to subsequently submit a variation to
update the product information of that product accordingly.
X.C.6. Transparency
Pursuant to Article 23 of Regulation 726/2004, the Agency will make publicly available the list of the
names and active substances of all medicinal products approved in the EU subject to additional
monitoring and the general criteria to include medicinal products in the list. The national competent
authority shall also make publicly available the list of medicinal products authorised in their territory
that are subject to additional monitoring.
The list will include an electronic link(s) to the relevant web-portal where the product information and
the summary of the RMP are publicly available.
29.07.2014
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22 January 2013
EMA/118465/2012
Guideline on good pharmacovigilance practices (GVP)
Module XV – Safety communication
Draft finalised by the Agency in collaboration with Member States and
submitted to ERMS FG
12 July 2012
Draft agreed by ERMS FG 20 July 2012
Draft adopted by Executive Director 25 July 2012
Start of public consultation 26 July 2012
End of consultation (deadline for comments) 21 September 2012
Revised draft finalised by the Agency in collaboration with Member
States
10 January 2013
Revised draft agreed by ERMS FG 16 January 2013
Revised draft adopted by Executive Director as final 22 January 2013
Date for coming into effect 24 January 2013
See websites for contact details
European Medicines Agency www.ema.europa.eu
Heads of Medicines Agencies www.hma.eu
The European Medicines Agency is
an agency of the European Union
© European Medicines Agency and Heads of Medicines Agencies, 2013.
Reproduction is authorised provided the source is acknowledged.
Table of contents
XV.A. Introduction ....................................................................................... 3
XV.B. Structures and processes ................................................................... 4
XV.B.1. Objectives of safety communication ................................................................... 4
XV.B.2. Principles of safety communication .................................................................... 4
XV.B.3. Target audiences ............................................................................................. 5
XV.B.4. Content of safety communication ...................................................................... 5
XV.B.5. Means of safety communication......................................................................... 6
XV.B.5.1. Direct healthcare professional communication (DHPC) ....................................... 6
XV.B.5.2. Documents in lay language ............................................................................ 7
XV.B.5.3. Press communication .................................................................................... 7
XV.B.5.4. Website ....................................................................................................... 8
XV.B.5.5. Other web-based communications .................................................................. 8
XV.B.5.6. Bulletins and newsletters ............................................................................... 8
XV.B.5.7. Inter-authority communication ....................................................................... 8
XV.B.5.8. Responding to enquiries from the public .......................................................... 8
XV.B.5.9. Other means of communication ...................................................................... 9
XV.B.6. Effectiveness of safety communication ............................................................... 9
XV.B.7. Quality system requirements for safety communication ........................................ 9
XV.C. Operation of the EU regulatory network ............................................. 9
XV.C.1. Coordination of safety announcements in the EU ................................................. 9
XV.C.1.1. Process for exchange and coordination of safety announcements ...................... 10
XV.C.1.2. Exchange of safety information produced by third parties ................................ 11
XV.C.1.3. Requirements for the marketing authorisation holder in the EU ........................ 12
XV.C.1.4. Consideration for third parties ...................................................................... 12
XV.C.1.5. Languages and translations ......................................................................... 12
XV.C.2. Direct healthcare professional communications in the EU .................................... 12
XV.C.2.1. Processing of DHPCs ................................................................................... 13
XV.C.2.2. Translation of DHPCs .................................................................................. 14
XV.C.2.3. Publication of DHPCs ................................................................................... 14
Figure VX.1: Flow chart for the processing of Direct Healthcare Professional Communications
(DHPCs) in the EU ..................................................................................................... 15
Guideline on good pharmacovigilance practices (GVP)– Module XV
EMA/118465/2012 Page 2/15
XV.A. Introduction
This Module provides guidance to marketing authorisation holders, competent authorities in Member
States and the European Medicines Agency on how to communicate and coordinate safety information
in the EU. Communicating safety information to patients and healthcare professionals is a public health
responsibility and is essential for achieving the objectives of pharmacovigilance in terms of promoting
the rational, safe and effective use of medicines, preventing harm from adverse reactions and
contributing to the protection of patients’ and public health (see Module I).
Safety communication is a broad term covering different types of information on medicines, including
statutory information as contained in the product information (i.e. the summary of product
characteristics (SmPC), package leaflet (PL) and the labelling of the packaging) and public assessment
reports. Although some principles in this Module (i.e. Section XV.B.1 and B.2.) apply to all types of
safety communication, the module itself focuses on the communication of ‘new or emerging safety
information’, which means new information about a previously known or unknown risk of a medicine
which has or may have an impact on a medicine’s benefit-risk balance and its condition of use. Unless
otherwise stated, the term ‘safety communication’ in this module should be read as referring to
emerging safety information.
Experience so far has demonstrated the need to coordinate safety communication within the EU
regulatory network. High levels of public interest are anticipated when new safety concerns arise and it
is important that clear and consistent messages are provided across the EU in a timely manner. The
new legislation on pharmacovigilance therefore includes a number of provisions to strengthen safety
communication and its coordination1.
Communication of important new safety information on medicinal products should take into account
the views and expectations of concerned parties, including patients and healthcare professionals, with
due consideration given to relevant legislation. This Module addresses some aspects of the interaction
with concerned parties and supplements the specific guidance given in Module XI on public
participation as well as the guidance on communication planning given in Module XII.
Communication is distinct from transparency, which aims to provide public access to information
related to data assessment, decision-making and safety monitoring performed by competent
authorities. The new EU legislation on pharmacovigilance envisages an unprecedented level of
transparency. Transparency provisions applicable to each pharmacovigilance process are provided in
the relevant GVP Modules.
Section XV.B. of this Module describes principles and means of safety communication. Section XV.C.
provides guidance on the coordination and dissemination of safety communications within the EU
network. Both sections give particular consideration to direct healthcare professional communications
(DHPCs), and provide specific guidance for preparing them. This is because of the central importance
of DHPCs in targeting healthcare professionals and because of the level of coordination required
between marketing authorisation holders and competent authorities in their preparation.
Throughout this Module, legal obligations are referred to as stated in the GVP Introductory Cover Note
and are usually identified by the modal verb ‘shall’ (e.g 'the marketing authorisation holder shall...').
When guidance is provided on how to implement legal provisions, the modal verb ‘should’ is used (e.g.
'the marketing authorisation holder should...'
1 Directive 2010/84/EU amending Directive 2001/83/EC (the latter is referenced as DIR), Regulation (EU) No 1235/2010
amending Regulation (EC) No 726/2004 (the latter is referenced as REG) and in the Commission Implementing Regulation
(EU) No 520/2012 on the Performance of Pharmacovigilance Activities Provided for in Regulation (EC) No 726/2004 and
Directive 2001/83/EC (the Implementing Regulation is referenced as IR).
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XV.B. Structures and processes
XV.B.1. Objectives of safety communication
Safety communication aims at:
• providing timely, evidence-based information on the safe and effective use of medicines;
• facilitating changes to healthcare practices (including self-medication practices) where necessary;
• changing attitudes, decisions and behaviours in relation to the use of medicines;
• supporting risk minimisation behaviour;
• facilitating informed decisions on the rational use of medicines.
In addition to the above effective, high quality safety communication can support public confidence in
the regulatory system.
XV.B.2. Principles of safety communication
The following principles of safety communication should be applied:
• The need for communicating safety information should be considered throughout the
pharmacovigilance and risk management process, and should be part of risk assessment (see
Module XII).
• There should be adequate coordination and cooperation between the different parties involved in
issuing safety communications (e.g. competent authorities, other public bodies and marketing
authorisation holders).
• Safety communication should deliver relevant, clear, accurate and consistent messages and reach
the right audiences at the right time for them to take appropriate action.
• Safety communication should be tailored to the appropriate audiences (e.g. patients and
healthcare professionals) by using appropriate language and taking account of the different levels
of knowledge and information needs whilst maintaining the accuracy and consistency of the
information conveyed.
• Information on risks should be presented in the context of the benefits of the medicine and include
available and relevant information on the seriousness, severity, frequency, risk factors, time to
onset, reversibility of potential adverse reactions and, if available, expected time to recovery.
• Safety communication should address the uncertainties related to a safety concern. This is of
particular relevance for emerging information which is often communicated while competent
authorities are conducting their evaluations; the usefulness of communication at this stage needs
to be balanced against the potential for confusion if uncertainties are not properly represented.
• Information on competing risks such as the risk of non-treatment should be included where
appropriate.
• The most appropriate quantitative measures should be used when describing and comparing risks,
e.g. the use of absolute risks and not just relative risks; for risk comparisons, denominators should
be the same in size. The use of other tools such as graphical presentation of the risk and/or the
benefit-risk balance may also be used.
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• Patients and healthcare professionals should, where possible, be consulted and messages pre-
tested early in the preparation of safety communication, particularly on complex safety concerns
(see Module XII).
• Where relevant safety communication should be complemented at a later stage with follow-up
communication e.g. on the resolution of a safety concern or updated recommendations.
• The effectiveness of safety communication should be evaluated where appropriate and possible
(see XV.B.7.).
• Safety communications should comply with relevant requirements relating to individual data
protection and confidentiality.
XV.B.3. Target audiences
The primary target audiences for safety communication issued by regulatory authorities and marketing
authorisation holders should be patients and healthcare professionals who use (i.e. prescribe, handle,
dispense, administer or take) medicinal products.
As primary target audiences, healthcare professionals play an essential role. Effective safety
communication enables them to give clear and useful information to their patients, thereby promoting
patient safety and confidence in the regulatory system. Both healthcare professionals in clinical
practice and those involved in clinical trials should be provided with appropriate information on any
safety concern at the same time.
Patient, consumer and healthcare professional organisations can play a role as multipliers as they can
disseminate important safety information to target audiences.
The media is also a target audience for safety communication. The capacity of the media to reach out
to patients, healthcare professionals and the general public is a critical element for amplifying new and
important information on medicines. The way safety information is communicated through the media
will influence the public perception and it is therefore important that the media receives safety
information directly from the competent authorities in addition to the information they receive from
other sources, such as from the marketing authorisation holders.
XV.B.4. Content of safety communication
Taking into account the principles in XV.B.2., safety communication should contain:
• important emerging information on any authorised medicinal product which has an impact on the
medicine’s benefit-risk balance under any conditions of use;
• the reason for initiating safety communication clearly explained to the target audience;
• any recommendations to healthcare professionals and patients on how to deal with a safety
concern;
• when applicable, a statement on the agreement between the marketing authorisation holder and
the competent authority on the safety information provided;
• information on any proposed change to the product information (e.g. the summary of product
characteristics (SmPC) or package leaflet (PL));
• a list of literature references, when relevant or a reference to where more detailed information can
be found;
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• where relevant, a reminder of the need to report suspected adverse reactions in accordance with
national spontaneous reporting systems.
The information in the safety communication shall not be misleading and shall be presented objectively
[DIR Art 106a(1)]. Safety information should not include any material or statement which might
constitute advertising within the scope of Title VIII of Directive 2001/83/EC.
XV.B.5. Means of safety communication
Communication tools and channels2 have become more numerous and varied over time, offering the
public more information than was previously possible. The use of this increasing variety of means
should be considered when issuing safety communication in order to reach the target audiences and
meet their growing expectations. Different communication tools and channels are discussed below in
sections XV.B.5.1.-XV-B.5.9.
XV.B.5.1. Direct healthcare professional communication (DHPC)
A direct healthcare professional communication (DHPC) is defined in this document as a
communication intervention by which important safety information is delivered directly to individual
healthcare professionals by a marketing authorisation holder or a competent authority, to inform them
of the need to take certain actions or adapt their practices in relation to a medicinal product. DHPCs
are not replies to enquiries from healthcare professionals, nor are they meant as educational material
for routine risk minimisation activities.
The preparation of DHPCs involves cooperation between the marketing authorisation holder and the
competent authority. Agreement between these two parties should be reached before a DHPC is issued
by the marketing authorisation holder. The agreement will cover both the content of the information
(see XV.B.4.) and the communication plan, including the intended recipients and the timetable for
disseminating the DHPC (see Module XII).
Where there are several marketing authorisation holders of the same active substance for which a
DHPC is to be issued, a single consistent message should normally be delivered.
Whenever possible, it is advised that healthcare professionals’ organisations or learned societies are
involved as appropriate during the preparation of DHPCs to ensure that the information they deliver is
useful and adapted to the target audience.
A DHPC may be complemented by other communication tools and channels and the principle of
providing consistent information should apply (XV.B.2.).
A DHPC may be an additional risk minimisation measure as part of a risk management plan (see
Modules V and XV).
A DHPC should be disseminated in the following situations when there is a need to take immediate
action or change current practice in relation to a medicinal product:
• suspension, withdrawal or revocation of a marketing authorisation for safety reasons;
• an important change to the use of a medicine due to the restriction of an indication, a new
contraindication, or a change in the recommended dose due to safety reasons;
• a restriction in availability or discontinuation of a medicine with potential detrimental effects on
patient care.
2 For the purpose of this section tools and channels are presented without distinction as they often overlap and there is no
general agreement on their categorisation.
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Other situations where dissemination of a DHPC should be considered are:
• new major warnings or precautions for use in the product information;
• new data identifying a previously unknown risk or a change in the frequency or severity of a known
risk;
• substantiated knowledge that the medicinal product is not as effective as previously considered;
• new recommendations for preventing or treating adverse reactions or to avoid misuse or
medication error with the medicinal product;
• ongoing assessment of an important potential risk, for which data available at a particular point in
time are insufficient to take regulatory action (in this case, the DHPC should encourage close
monitoring of the safety concern in clinical practice and encourage reporting, and possibly provide
information on how to minimise the potential risk).
A competent authority may disseminate or request the marketing authorisation holder to disseminate a
DHPC in any situation where the competent authority considers it necessary for the continued safe and
effective use of a medicinal product.
XV.B.5.2. Documents in lay language
Communication material in lay language (e.g. using a questions & answers format) helps patients and
the general public to understand the scientific evidence and regulatory actions relating to a safety
concern. Lay language documents should contain the competent authority’s recommendations and
advice for risk minimisation for patients and healthcare professionals in relation to the safety concern,
and should be accompanied by relevant background information.
Lay language documents are generally useful to members of the public who have an interest in the
subject but do not have a scientific or regulatory background. Reference should be made to other
communication materials on the topic to direct readers to where they can find further information.
Competent authorities publish lay language documents on their national medicines web-portals and
may additionally disseminate them to relevant parties such as patients and healthcare professionals’
organisations.
Whenever possible, it is advised that patients and healthcare professionals are involved during the
preparation of lay language documents to ensure that the information they deliver is useful and
adapted to the target audience.
XV.B.5.3. Press communication
Press communication includes press releases and press briefings which are primarily intended for
journalists.
Competent authorities may send press releases directly to journalists in addition to publishing them on
their websites. This ensures that journalists, in addition to obtaining information from other sources,
receive information that is consistent with the authority’s scientific assessment. Interaction with the
media is an important way to reach out to a wider audience as well as to build trust in the regulatory
system.
Press releases may also be prepared and published by marketing authorisation holders. Their press
releases may reflect the position of the marketing authorisation holder on a safety topic but should
also make reference to any regulatory action taken by the competent authority. Relevant ongoing
reviews should be mentioned in any communication by the marketing authorisation holder.
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Although aimed at journalists, press releases will be read by other audiences such as healthcare
professionals, patients and the general public. Reference should therefore be made to related
communication materials on the topic. In cases where a DHPC is also prepared, healthcare
professionals should ideally receive it prior to or around the same time of the publication or distribution
of a press release so that they are better prepared to respond to patients.
Press briefings with journalists should be considered by competent authorities for safety concerns or
other matters relating to the safety of medicinal products that are of high media interest or when
complex or public-health-sensitive messages need to be conveyed.
XV.B.5.4. Website
A website is a key tool for members of the public (including patients and healthcare professionals)
actively searching the internet for specific information on medicinal products. Competent authorities as
well as marketing authorisation holders should ensure that important safety information published on
websites under their control is easily accessible and understandable by the public. Information on
websites should be kept up-to-date, with any information that is out-of-date marked as such or
removed.
The new legislation on pharmacovigilance foresees the creation of an EU medicines web portal which
will contain information on all medicines authorised in the EU [Article 26 of Regulation (EU) No
1235/2010]. This web portal will become a key tool for communicating up-to-date safety information
to EU citizens and will contain information in all EU official languages. Each Member State shall set up
and maintain a national medicines web-portal which shall be linked to the EU medicines web-portal.
[DIR Art 106a]. Until the web portal is fully established and into operation, the Agency’s website will be
acting as an interim platform to convey this important up-to-date safety information.
XV.B.5.5. Other web-based communications
Online safety information may also be disseminated via other web tools. When using newer, more
rapid communication channels, special attention should be paid to ensure that the accuracy of the
information released is not compromised. Communication practices should take into account emerging
communication tools used by the various target audiences.
XV.B.5.6. Bulletins and newsletters
Bulletins and newsletters provide at regular intervals new information about medicines and their safety
and effectiveness. Competent authorities can reach a large audience with these tools by using web-
based and other available means.
XV.B.5.7. Inter-authority communication
When one competent authority takes regulatory action on a particular safety concern, other competent
authorities usually need to respond to enquiries or communicate on the same issue. The use of inter-
authority communication material, such as lines-to-take should be considered. Lines-to-take are
documents specifically prepared by a competent authority to assist its own staff and those of co-
operating authorities in responding to external enquires or communicating on a specific safety issue.
XV.B.5.8. Responding to enquiries from the public
Competent authorities and marketing authorisation holders should have systems in place for
responding to enquiries about medicines from individual members of the public. Responses should take
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into account the information which is in the public domain and should include the relevant
recommendations to patients and healthcare professionals issued by competent authorities. Where
questions relate to individual treatment advice, the patient should be advised to contact a healthcare
professional.
In this respect, Article 86(2) and Article 98(1) of Directive 2001/83/EC apply to marketing
authorisation holders.
XV.B.5.9. Other means of communication
In addition to those discussed above, there are other tools and channels such as publications in
scientific journals and journals of professional bodies.
Some tools and channels may be used in the context of risk management; risk minimisation measures
often include specific programmes for risk communication. Tools used in such programmes, such as
patient alert cards or healthcare professional safety guidance, are outside the scope of this module and
are described in more detail in Module XVI.
XV.B.6. Effectiveness of safety communication
Safety communication is considered effective when the message transmitted is received and
understood by the target audience in the way it was intended, and appropriate action is taken by the
target audience. Adequate mechanisms should be introduced in order to measure the effectiveness of
the communication based on clear objectives. Measuring effectiveness allows lessons to be learned and
helps in making decisions on prioritising and adapting tools and practices to meet the needs of the
target audiences. A research-based approach will normally be appropriate in order to establish that
safety communications have met the standard of XV.B.2. This approach may measure different
outcomes, including behaviour, attitudes, and knowledge. When evaluating the effectiveness of safety
communication, the scope of the evaluation may be broadened to include factors other than the
performance of the individual tools used in the safety communication (see Module XVI).
In the case of DHPCs, the marketing authorisation holder should be responsible for evaluating the
dissemination of the DHPCs they prepare and should inform the competent authorities of the outcome
and of any difficulties identified (e.g. problems related to the list of recipients or the timing and
mechanism of dissemination). Appropriate action should be taken as needed to correct the situation or
prevent similar problems in the future.
XV.B.7. Quality system requirements for safety communication
In accordance with the quality system requirements in Module I, procedures should be in place to
ensure that safety communications comply with the principles in XV.B.2. as appropriate.
In particular, the communications should be subject to quality controls to ensure their accuracy and
clarity. For this purpose review procedures with allocated responsibilities should be followed and
documented.
XV.C. Operation of the EU regulatory network
XV.C.1. Coordination of safety announcements in the EU
In the EU, patients and healthcare professionals increasingly look at competent authorities as providers
of important information on medicines. For safety communication to be effective, adequate
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coordination and cooperation is required within the EU regulatory network3. A good level of
coordination of safety communication is of particular importance so that healthcare professionals and
patients receive consistent information on regulatory decisions in the EU.
When issuing safety announcements, competent authorities may make use of the different tools and
channels described in XV.B.5. Prior to the publication of a safety announcement, the Member States,
the Agency or the European Commission shall inform each other not less than 24 hours in advance,
unless urgent public announcements are required for the protection of public health [DIR Art 106a(2)].
For active substances contained in medicinal products authorised in more than one Member State, the
Agency shall be responsible for the coordination between national competent authorities of safety
announcements [DIR Art 106a(3)].
For practical reasons, considering the potential for overlap between transparency measures and active
communications and in order to focus on those topics of major health relevance, not all safety
information made public by a Member State or the Agency will be subject to systematic exchange and
coordination. Only safety announcements that relate to the following and that pertain to active
substances contained in medicinal products authorised in more than one Member State require
coordination within the EU regulatory network:
• the suspension, withdrawal or revocation of a marketing authorisation due to changes to its
benefit-risk balance;
• the start or finalisation of an EU referral procedure for safety reasons;
• restriction of indication or treatment population or the addition of a new contraindication;
• dissemination of a DHPC agreed by relevant competent authorities of a Member State or the
Agency (see XV.C.2.1.);
• other emerging safety concerns judged by a national competent authority or the Agency to be
likely to give rise to public or media interest in more than one Member State (e.g. a publication of
important safety findings in a (scientific) journal, safety-related regulatory action taken in a
Member State or in a country outside the EU).
XV.C.1.1. Process for exchange and coordination of safety announcements
A competent authority of a Member State or the Agency shall inform the EU regulatory network prior to
the publication of a safety announcement that pertains to active substances contained in medicinal
products authorised in more than one Member State and that refer to any of the situations identified in
XV.C.1. It shall include a timetable for the information being made public [DIR Art 106a(3)]. Whenever
possible the safety announcement shall be sent to the network under embargo no less than 24 hours in
advance of publication [DIR Art 106a (2)], in order to allow the members of the EU regulatory network
to prepare or plan their own communication if necessary. Under the coordination of the Agency, the
Member States shall make all reasonable efforts to agree on a common message [DIR Art 106a(3)].
The Agency should decide for each case, on the basis of the public health relevance and urgency of the
safety concern, the population and number of Members States affected and the potential for media
attention, whether further action in addition to the dissemination of the safety announcement is
needed, such as:
3 i.e. the competent authorities in the Member States, the Agency and the European Commission.
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• the preparation of lines-to-take (see XV.B.5.7.) which should be disseminated to the EU regulatory
network. The lines-to-take document should help the EU regulatory network to respond to any
request for information which may follow the publication of the safety announcement;
• the preparation of an Agency safety announcement in addition to that of the Member State, which
should also be disseminated under embargo to the EU regulatory network together with a
timetable for its publication.
The Agency should prepare lines-to-take documents and any Agency safety announcement together
with the Member State(s) who originated the process and the PRAC Lead Member State or the PRAC
Rapporteur, as appropriate. The PRAC, as well as the CHMP or CMDh, should also be consulted as
necessary.
Coordination of safety announcements should be done in cooperation with the concerned marketing
authorisation holder(s). Whenever possible, the Agency and the competent authorities in Member
States should provide any safety announcement prior to its publication to the concerned marketing
authorisation holder(s), together with the timetable for the information being made public. Any
information of a personal or commercially confidential nature shall be deleted unless its public
disclosure is necessary for the protection of public health [DIR Art 106a (4)].
The exchange and coordination of safety announcements within the EU regulatory network should
make use of the EU Early Notification System (ENS). The ENS was developed for use by the Agency to
provide advance notice to competent authorities in Member States and the European Commission of
safety information on centrally authorised products. This system should also be used by competent
authorities in Member States for the purpose of exchanging and coordinating safety announcements.
The ENS includes the Heads of Medicines Agencies (HMA), the members of the PRAC, CHMP, CMDh,
the operational contact points for safety announcements at the competent authority in Member States,
the European Commission and the Agency. Operational contact points should ensure that any
information exchanged via the system reaches in a timely manner the relevant staff within each
competent authority, including relevant staff working within the communications departments.
Safety announcements from the EU regulatory network should be shared with international partners in
accordance with the guidance provided in Module XIV, subject to embargo and any specific
confidentiality arrangements in place.
As a complement to the coordination of safety announcements within the EU regulatory network,
competent authorities in Member States and the Agency should interact with concerned stakeholders in
the EU (mainly patients’ and healthcare professionals’ organisations), who can play a key role in
reviewing and disseminating information to the end users (patients and healthcare professionals). It is
recommended that national competent authorities and the Agency keep up-to-date contact details of
relevant patients, and healthcare professionals’ organisations.
XV.C.1.2. Exchange of safety information produced by third parties
There are situations where emerging safety information is to be published or has been published by a
party other than a competent authority of a Member State or the Agency (e.g. scientific journals,
learned societies). Competent authorities should bring to the attention of the EU regulatory network
any such safety information that they become aware of, together with the timing of the publication if
known. Where necessary and after evaluation of the information, the Agency should prepare and
disseminate a lines-to-take document or an Agency safety announcement to address the information
from the third party (see XV.C.1.1.).
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In the context of collaboration with authorities outside the EU, the Agency or a competent authority of
a Member State may become aware of safety announcements to be published by these authorities (see
Module XIV). In these cases the Agency should, as necessary, prepare and disseminate lines-to-take or
safety announcements within the EU regulatory network. In all cases, the terms of any relevant
confidentiality agreements with non-EU regulatory authorities and the embargoes on the information
received should be respected.
XV.C.1.3. Requirements for the marketing authorisation holder in the EU
As soon as a marketing authorisation holder in the EU intends to make a public announcement relating
to information on pharmacovigilance concerns in relation to the use of a medicinal product, and in any
event at the same time or before the public announcement is made, the marketing authorisation
holder shall be required to inform the competent authorities in Member States, the Agency and the
European Commission [DIR Art 106a]. This should apply to announcements intended for the EU as well
as outside the EU (when they concern products authorised in the EU or those for which an opinion
under Article 58 of Regulation (EC) 726/2004 has been given). Informing the authorities at the same
time as the public (i.e. without advance notice to the authorities) should only occur exceptionally and
under justified grounds. Whenever possible, the information should be provided under embargo at
least 24 hours prior to its publication.
The marketing authorisation holder shall ensure that information to the public is presented objectively
and is not misleading [DIR Art 106a].
Whenever a marketing authorisation holder becomes aware that a third party (see XV.C.1.2.) intends
to issue communication that could potentially impact the benefit-risk balance of a medicinal product
authorised in the EU, the marketing authorisation holder should inform the relevant competent
authorities in Member States and the Agency and make every effort to share the content of the
communications with the relevant authorities.
XV.C.1.4. Consideration for third parties
Third parties (e.g. scientific journals, learned societies, patients’ organisations) are encouraged to
inform the Agency and the competent authorities in Member States of any relevant emerging
information on the safety of medicines authorised in the EU and, if publication is planned, to share the
information ahead of publication.
XV.C.1.5. Languages and translations
Consistent messages should reach the public across the EU in a timely manner and in the official
languages of the Member States as specified by the Member States where the medicinal product is
placed on the market.
For the purpose of coordination, the Agency shall use English to inform the EU regulatory network of
any safety announcement. When informing the Agency, the competent authorities in Member States
are encouraged to provide English translations of their safety announcements for the purpose of
initiating the coordination process. In the absence of a full text translation, an English summary should
be provided.
XV.C.2. Direct healthcare professional communications in the EU
In the EU, a direct healthcare professional communication (DHPC) (see XV.B.5.1.) is usually
disseminated by one or a group of marketing authorisation holders for the respective medicinal
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product(s) or active substance(s), either at the request of a national competent authority or the
Agency, or on the marketing authorisation holder’s own initiative. The marketing authorisation holder
should seek the agreement of the relevant national competent authorities or the Agency regarding the
content of a DHPC (and communication plan) prior to dissemination.
XV.C.2.1. Processing of DHPCs
The situations when a DHPC is necessary or should be considered are provided in XV.B.5.1. When
drafting a DHPC, the template (see Annex II) and the guidance provided in the annotations in the
template should be followed as appropriate.
The roles and responsibilities of the competent authorities in a Member State, the Agency and
marketing authorisation holders in the preparation and processing of DHPCs depend on the route of
authorisation of the medicinal products concerned:
• for centrally authorised products and for products subject to an EU referral procedure for safety
reasons, the relevant marketing authorisation holders should submit the draft DHPC and
communication plan (including the intended recipients and the timetable for disseminating the
DHPC) to the Agency, which should coordinate the review process by its scientific committees (i.e.
PRAC and CHMP) and CMDh.
• for products authorised through the mutual recognition or decentralised procedure, the marketing
authorisation holder should submit the draft DHPC and communication plan to the Reference
Member State, which should co-ordinate the process with the marketing authorisation holder, while
keeping the Concerned Member States informed of any proposed action.
• for nationally authorised products not authorised through the mutual recognition or decentralised
procedure, the marketing authorisation holder should submit the draft DHPC and any
communication plan to the competent authorities of the Member States where the products are
authorised.
The marketing authorisation holder should allow a minimum of two working days for comments.
However, whenever possible more time should be allowed. The timing may be adapted according to
the urgency of the situation.
The Agency will coordinate the review of DHPCs within its scientific committees/groups as appropriate
(i.e. involvement of PRAC, and finalisation by CHMP or CMDh) The PRAC should always be involved in
the review of DHPCs related to a safety concern being discussed at the PRAC and the DHPC should
form part of the PRAC assessment (see Module XII). The Agency may also request advice from the
PRAC on issues related to other safety communications.
Once the content of a DHPC and communication plan from the MAH are agreed by national competent
authorities or the Agency, the national competent authorities or the Agency should exchange the final
DHPC and communication plan using the early notification system (see XV.C.1.1.), and the Agency
should coordinate any subsequent safety announcement as appropriate using the process described in
XV.C.1.1. The early notification system is only used if the DHPC concerns an active substance
authorised in more than one Member State.
In cases where an authority outside the EU requests the dissemination of a DHPC in their territory for a
product also authorised in the EU, the marketing authorisation holder should notify the relevant
competent authorities in the EU. This is part of the legal requirement under which the marketing
authorisation holder shall notify the competent authorities of any new information which may impact
the benefit-risk balance of a medicinal product [REG Art 16(2) and DIR 23(2)]. The need for any
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subsequent communication, e.g. a DHPC, in the EU should be considered and agreed on a case-by-
case basis.
A flow chart describing the processing of DHPCs is provided in Figure XV.I at the end of the Module.
XV.C.2.2. Translation of DHPCs
For centrally authorised products, products subject to an EU referral procedure for safety reasons and,
in most cases, for products authorised through the mutual recognition or decentralised procedure, the
working language for preparing the DHPCs will normally be English.
Once the text of the DHPC is agreed, the marketing authorisation holder should prepare translations in
the official languages of the Member States, as specified by the Member States where the DHPC is to
be distributed. The draft translations should be submitted to the Member States for a language review
within a reasonable timeframe (no more than two working days).
For centrally authorised products and products subject to an EU referral procedure for safety reasons,
the relevant marketing authorisation holder should provide the Agency with a complete set of all final
EU official language versions as well as any additional related communication documents.
XV.C.2.3. Publication of DHPCs
The competent authorities may publish the final DHPC. The timing for such publication should be
aligned to that of the dissemination of DHPC in the Member States. The competent authorities may
also issue an additional safety announcement, and disseminate the DHPC to relevant healthcare
professionals’ organisations as appropriate.
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Identification of need of
DHPC according to criteria in
XV.B.5.1.
Issue concerns
CAPs or
products
subject to EU
referral
procedure
MAH to submit draft DHPC
and communication plan to
Agency (allowing at least 2
working days for comments)
Issue concerns
products
authorised via
MR or DP
Issue
concerns
NAPs
MAH to submit draft DHPC
and communication plan to
Reference Member State
(allowing at least 2 working
days for comments)
MAH to submit draft
DHPC and
communication plan to
NCA (allowing at least 2
working days for
comments)
DHPC and communication
plan agreed at Agency level1
DHPC and communication
plan agreed by Reference
Member State in
collaboration with Concerned
Member States
DHPC and
communication plan
agreed by NCA
Agency to circulate agreed
DHPC within the EU
regulatory network
Reference Member State to
circulate agreed DHPC within
the EU regulatory network
NCA to circulate agreed
DHPC within the EU
regulatory network (only
if concerned product is
authorised in more than
1 Member State)
MAH to arrange translation
and distribution of DHPC with
NCAs according to agreed TT
MAH to arrange translation
and distribution of DHPC with
NCAs according to agreed TT
MAH to arrange
translation and
distribution of DHPC with
NCAs according to
agreed TT
YES YES
YES
NONO
1 The Agency will coordinate the review of DHPC within its
scientific committees (i.e. PRAC and CHMP) and CMDh.
Figure VX.1: Flow chart for the processing of Direct Healthcare Professional Communications
(DHPCs) in the EU
Guideline on good pharmacovigilance practices (GVP)– Module XV
EMA/118465/2012 Page 15/15
XV.A. Introduction
XV.B. Structures and processes
XV.B.1. Objectives of safety communication
XV.B.2. Principles of safety communication
XV.B.3. Target audiences
XV.B.4. Content of safety communication
XV.B.5. Means of safety communication
XV.B.5.1. Direct healthcare professional communication (DHPC)
XV.B.5.2. Documents in lay language
XV.B.5.3. Press communication
XV.B.5.4. Website
XV.B.5.5. Other web-based communications
XV.B.5.6. Bulletins and newsletters
XV.B.5.7. Inter-authority communication
XV.B.5.8. Responding to enquiries from the public
XV.B.5.9. Other means of communication
XV.B.6. Effectiveness of safety communication
XV.B.7. Quality system requirements for safety communication
XV.C. Operation of the EU regulatory network
XV.C.1. Coordination of safety announcements in the EU
XV.C.1.1. Process for exchange and coordination of safety announcements
XV.C.1.2. Exchange of safety information produced by third parties
XV.C.1.3. Requirements for the marketing authorisation holder in the EU
XV.C.1.4. Consideration for third parties
XV.C.1.5. Languages and translations
XV.C.2. Direct healthcare professional communications in the EU
XV.C.2.1. Processing of DHPCs
XV.C.2.2. Translation of DHPCs
XV.C.2.3. Publication of DHPCs
Figure VX.1: Flow chart for the processing of Direct Healthcare Professional Communications (DHPCs) in the EU
29.07.2014
Datei
PD
